Chemotherapy-induced Peripheral Neuropathy (CIPN)

Part
01
of two
Part
01

Chemotherapy-induced Peripheral Neuropathy - Part One

The main cause of Chemotherapy-induced Peripheral Neuropathy (CIPN) is adverse effects that occur because of the use of chemotherapy drugs. This may last for years even after termination of chemotherapy. Approximately 48% of cancer patients who receive chemotherapy are diagnosed with Chemotherapy-induced Peripheral Neuropathy (CIPN).

After conducting an in-depth search through various cancer and chemotherapy sites such as UCSF Health.org, Cancer.net, Cancer.org, Medical News Today, Mayo Clinic, Clinical Trials.gov, and Peripheral Neuropathy research article, we have established that the information on demographic statistics specifically on age, gender, and ethnicity, and the disease history for Chemotherapy-induced Peripheral Neuropathy (CIPN) is not available publicly. Below we have discussed our research methodology including how we searched and why some of the required information is not available publicly.

METHODOLOGY

Initially, our research team searched for information on the epidemiology, demographic statistics, and disease history of Chemotherapy-induced Peripheral Neuropathy (CIPN) and could locate the information on the causality of Chemotherapy-induced Peripheral Neuropathy (CIPN) precompiled through credible sources. However, the information on epidemiology, demographic statistics, and disease history was very limited in the public domain. The research was conducted through reports and articles obtained from Chemotherapy-induced Peripheral Neuropathy institutes, cancer organizations, healthcare articles such as cancer.org, ASCO Pubs, Medscape, NCBI, cancer.gov, US census, and others. Most of the information we found was related to the clinical trials of drugs induced for CIPN.

Later, we searched CIPN market reports through various business articles and pharma company publications to find the information on epidemiology in various sites such as Global NewsWire, PR NewsWire, MarketWatch, Abbott, Pfizer, GSK, and others. Through this search, we were able to locate one of the reports published by Global NewsWire which revealed that in 2016, there were 100,000 to 300,000 Chemotherapy-induced Peripheral Neuropathy patients and the incidence rate (or growth rate) is at 0.35% (CAGR). So, we used this data and calculated the prevalence of CIPN patients for 2018.

As there was no direct information on the incidence, and the prevalence of CIPN we have provided the above statistics as an approximate value.

Information on demographic statistics and disease history of Chemotherapy-induced Peripheral Neuropathy was not available due to the reason that unlike other diseases CIPN is not common for all population and very specific for patients with chemotherapy. So, the research is very niche to derive further segmentation by age, gender, ethnicity, and history. This might be the reason no research reports, survey articles, news articles, or other media articles have not mentioned this information anywhere. Below are the strategies we applied to search the required data:

Based on Initial search, we could conclude that this disease is not common for all population and very specific for patients with chemotherapy. So, we tried to locate the statistics on the number of patients who received chemotherapy by age, gender, ethnicity and could locate recent cancer statistics by gender which did not show much variation by gender. So, we could not identify any insights on statistics of chemotherapy while searching through various cancer and chemotherapy sites such as UCSF Health.org, Cancer.net, Cancer.org, Medical News Today, Mayo Clinic, Clinical Trials.gov, and others.

Further, we tried to derive the segmentation or classification of Chemotherapy-induced Peripheral Neuropathy (CIPN) by age, gender, ethnicity from Peripheral Neuropathy research articles and could locate most of the information on Diabetic peripheral neuropathy and Peripheral Neuropathy in general. But no further segmentation details were found while searching through Cleveland Clinic Med, DMS Journal, AAFP, BMJ, NCBI, ASCO Pubs, etc.

Then, we expanded the scope of our research beyond the standard timeline of 24 months as details on demographic statistics, and disease history of Chemotherapy-induced Peripheral Neuropathy may be varied minimally by the timeline. However, through this strategy also, we could only locate information on treatment, diagnosis etc. but nothing specific to age, gender, ethnicity and history while searching through various websites such as US Census, WHO, Clinical Trials.gov, NCBI, PJIAP, Semantic Scholar, ASCO, WCRF, Cancer.gov, Medicalxpress, Online Library Wiley, etc.

After conducting an in-depth search through the above-mentioned strategy, we have established that the information on demographic statistics and disease history of Chemotherapy-induced Peripheral Neuropathy are not available publicly.

Chemotherapy-induced Peripheral Neuropathy (CIPN)

1. EPIDEMIOLOGY

Incidence: There were 100,000 to 300,000 Chemotherapy-induced Peripheral Neuropathy patients in 2016 and the incidence rate (or growth rate) was 0.35% (CAGR).

Therefore, average CIPN cases in 2016 can be calculated as 200,000 (100,000 + 300,000/2) and the growth rate (CAGR) is 0.35%. Using an online calculator, we have calculated the number of CIPN patients in the US to be 201,402 in 2018.

Prevalence: The rate of prevalence in CIPN patients varies as follows:

In patients with 1-month of chemotherapy, the prevalence of CIPN is 68.1%.
In patients with 3-months of chemotherapy, the prevalence of CIPN is 60%.
In patients with 6-months of chemotherapy, the prevalence of CIPN is 30%.

Approximately, 48% of cancer patients who receive chemotherapy are diagnosed with Chemotherapy-induced Peripheral Neuropathy.

DEMOGRAPHIC STATISTICS

Based on our research, we have established that the information on demographic statistics specifically on age, gender, and ethnicity for CIPN patients is not available publicly. However, our research concluded that there is no significant difference in the incidence and prevalence of chemotherapy-induced peripheral neuropathy in women with chemotherapy-induced peripheral neuropathy by race or ethnicity or poverty.

DISEASE HISTORY/CAUSALITY

Causality: The main cause of Chemotherapy-induced Peripheral Neuropathy (CIPN) is the adverse effect caused by drugs which are used during chemotherapy and this may last for years even after termination of chemotherapy.





Part
02
of two
Part
02

Chemotherapy-induced Peripheral Neuropathy - Part Two

As far as chemotherapy-induced peripheral neuropathy (CIPN) is concerned, 26 treatments have been studied so far, and only duloxetine and photobiomodulation have been found to be of some benefit or effectiveness. Duloxetine is the only treatment recommended by the American Society of Clinical Oncology (ASCO), and the rest of the treatments that were studied are used in an off-label manner. As there is no existing treatment that is especially effective, the unmet needs of CIPN patients center on a demand for treatments that can effectively eliminate or lessen the pain, numbness, and weakness they are experiencing.

AVAILABLE TREATMENTS

Published in the journal Pain Physician in 2018, a systematic review of literature on the treatment of CIPN shows there are 26 treatment options available. Spanning pharmacologic therapy and other modalities, these treatment options are as follows: IV infusion acetyl-l-carnitine (ALC), amitriptyline, cannabinoid, duloxetine, gabapentin, lamotrigine, IV infusion lidocaine, neurofeedback (NFB), nortriptyline, OPERA (new dietary supplement), long-acting oxycodone, palmitoylethanolamide, photobiomodulation (PBM) laser therapy, venlafaxine, topical 2% amitriptyline and 4% ketamine, topical baclofen, amitriptyline and ketamine (BAK-PLO), topical menthol (TRPM8
agonist), acupuncture, electro-acupuncture, laser acupuncture (LA), percutaneous auricular neurostimulation (PANS), acupuncture like transcutaneous nerve stimulation (ALTENS), sweet bee venom pharmacopuncture (SBVP), interferential therapy and long-wave diathermy at high power (ITH), low frequency magnetic field therapy, and scrambler therapy.

Less specific treatment names can be seen on the American Cancer Society's primer for managing peripheral neuropathy. According to this primer, the treatment categories are steroids, numbing patches or creams, anti-depressants, anti-seizure drugs, and opioids or narcotics. These drugs are typically given to CIPN patients for pain relief. Other treatments that can be used in easing nerve pain include electrical nerve stimulation, occupational therapy, physical therapy, relaxation therapy, guided imagery, distraction, acupuncture, and biofeedback.

EFFECTIVENESS OF TREATMENTS

Based on the aforementioned systematic review, no recommendations can be made regarding 22 of the treatment options due to insufficient evidence. Recommendations can be made for only the following four treatment options: duloxetine, lamotrigine, photobiomodulation (PBM) laser therapy, and topical 2% amitriptyline and 4% ketamine. There is evidence that, in the treatment of CIPN, duloxetine or photobiomodulation (PBM) laser therapy offers moderate or modest benefit, and lamotrigine and especially topical 2% amitriptyline and 4% ketamine should not be used. The only treatment recommended by the ASCO is duloxetine. Duloxetine belongs to the category of drugs known as serotonin-norepinephrine reuptake inhibitors (SNRIs). An anti-depressant that comes in oral capsule form only, duloxetine is used to treat depression, anxiety, fibromyalgia, chronic muscle pain and joint pain, and diabetes nerve pain.

A study published in the Annals of Neurology in 2017 shows that other CIPN treatments, such as gabapentin and the topical preparations mentioned in the previous section, are used in an off-label manner. While the treatments themselves are approved by a regulatory authority, there is no regulatory approval of their use in the treatment of CIPN. Market research firm Research and Markets even says "there is no approved therapy for the treatment of CIPN" and the existing therapeutic landscape relies on off-label treatment options.

An article published by The University of Texas MD Anderson Center shows that while there are several treatment options available for CIPN, "none of these options are especially effective, and all have adverse effects." Moreover, according to Sarah Prinsloo, Ph.D., an assistant professor specializing in palliative, rehabilitative, and integrative medicine, "there aren't a lot of effective treatments on the market for it."

A study published in the British Journal of Anaesthesia in 2017 also states that there is limited evidence of effective CIPN treatments. For management of CIPN to be most effective, combination therapies may have to be used, and oncology and pain management teams must work closely together in determining the best treatment for their patients.

UNMET NEEDS OF CIPN PATIENTS

The greatest unmet need of CIPN patients appears to be the need for treatments that can effectively alleviate CIPN. "There is an unmet need for treatments that can alleviate CIPN," according to a report released by the ASCO. Also, according to Apexian Pharmaceuticals' recent press release, "CIPN is a disease with high unmet need." When asked about the biggest unmet need of patients, Dr. Ahmet Hoke, a neurology and neuroscience professor at Johns Hopkins, explains that the most common complaint of chemotherapy patients with peripheral neuropathy is pain in the feet. This is followed by injuries and loss of balance due to numbness. Patients, particularly those with advanced neuropathy, also complain of muscle weakness, especially in the ankles. While peripheral neuropathy is rarely fatal, it can make the lives of patients miserable. According to Hoke, some patients even wished they did not undergo chemotherapy because the pain brought about by CIPN was excruciating.

Dr. Steven Scherer, a neurology professor at the University of Pennsylvania who has almost 40 years of experience with neuropathy treatment, adds that "peripheral neuropathies rob people of the motor and sensory functions of their distal extremities." And the pain, weakness, and numbness typically progress upwards. In severe cases, autonomic dysfunctions, including feet turning purple, can occur. In essence, CIPN patients need treatments that can effectively stop or alleviate the pain, weakness, and numbness.

Additional information may be found in an editorial commentary published in the Journal of Neurology, Neurosurgery, and Psychiatry in 2017. This editorial commentary specifically covers unmet needs as far as CIPN is concerned. The article is paywalled, however.

Sources
Sources

From Part 01
Quotes
  • "Some of the chemotherapy and other drugs used to treat cancer can damage peripheral nerves. When this happens it is called chemotherapy-induced peripheral neuropathy (CIPN). This can be a disabling side effect of cancer treatment. "
  • "CIPN can cause severe pain and can affect your ability to do things like walk, write, button your shirt, or pick up coins. CIPN can last for weeks, months, or even years after treatment is done. If it gets very bad, it can cause more serious problems like changes in your heart rate and blood pressure, dangerous falls, trouble breathing, paralysis, or organ failure."
Quotes
  • "prevalence of CIPN was 68.1% (95% CI 57.7–78.4%) when measured in the first month after chemotherapy completion, 60.0% (95% CI 36.4–81.6%) at 3 months, and 30.0% (95% CI 6.4–53.5%) at 6 months or more"
Quotes
  • " CIPN prevalence was 68.1% (95% CI=57.7-78.4) within the first month of the end of chemotherapy, 60.0% (36.4-81.6) at 3 months, and 30.0% (6.4-53.5) at 6 months or later. "
Quotes
  • "In 2016, incident cases of mild, moderate and severe CIPN in the US varied in the range 100,000 to 300,000."
  • "incident population of CIPN in the G8 countries is expected to increase at a CAGR of 0.35% for the study period i.e. 2016-2027."
Quotes
  • "CIPN is a common treatment-related adverse effect, affecting up to 48% of cancer patients who received chemotherapy"
Quotes
  • "The CIPN incidence rate was higher for women who at the time of their breast cancer diagnosis were relatively young (within this Medicare sample), were at AJCC stage II or III, were married or had an equivalent status, and had fewer comorbidities, but it did not differ by race/ethnicity or poverty level."
From Part 02
Quotes
  • "Treatment can often help ease some of the symptoms of CIPN. Sometimes these symptoms go away a short time after treatment is done. But sometimes they last much longer and need long-term treatment."
  • "Severe CIPN may never go away."
  • "Treatment is mostly given to relieve the pain that can come with CIPN."
  • "Researchers are looking at which drugs work best to relieve this kind of pain. It may take more than one try to find out what works best for you."
Quotes
  • "Most cases are treated with a combination of antidepressants, anticonvulsants, and analgesics. Topical numbing agents such as lidocaine are sometimes used, and opioids may be prescribed in cases involving extreme pain. However, none of these options are especially effective, and all have adverse effects."
  • "“Neuropathy is a pretty pervasive problem; it can happen to patients with any type of cancer and be caused by many types of chemotherapy,” said Sarah Prinsloo, Ph.D., assistant professor of Palliative, Rehabilitation, and Integrative Medicine. “And there aren’t a lot of effective treatments on the market for it.”"
Quotes
  • "A report from the American Society for Clinical Oncology states that there is an unmet need for treatments that can alleviate CIPN."
Quotes
  • "Pain in the feet is by far the most common complaint in particular in diabetes and chemotherapy patients. The loss of balance and injuries caused by numbness also are big problems. I tell patients to always make sure they check the bottom of their feet with a mirror every night and keep it clean because they could easily step on something sharp and develop a non-healing ulcer."
  • "With advanced neuropathy, patients also can develop muscle weakness, especially with their ankles, that can cause them to trip and fall."
  • "Peripheral neuropathies rob people of the motor and sensory functions of their distal extremities. This causes weakness, pain and numbness, which often progresses by moving up the feet and hands. Severe neuropathies can also cause autonomic dysfunctions, such as the feet turning purple because of the loss of blood vessel control."
  • "Peripheral neuropathies rarely kill people but can make their lives miserable. Several patients told me they would rather have not had their chemotherapy treatments and risked their survival because the pain from their neuropathy was so severe."
Quotes
  • "There are no effective strategies to prevent CIPN, with limited evidence of effective drugs for treating established CIPN. Duloxetine has moderate evidence, with extrapolation from other neuropathic pain states generally being used to direct treatment options for CIPN."
  • "Thus, combination therapies may well be required for most effective management. More effective treatment of CIPN will require closer links between oncology and pain management clinical teams to ensure CIPN patients are effectively monitored. Furthermore, continued close collaboration between clinical and preclinical research will facilitate the development of novel treatments for CIPN."
Quotes
  • "For the present, treatment of CIPN relies on reducing or discontinuing the offending agent when CIPN develops and treating the symptoms of neuropathic pain."
  • "The National Cancer Institute has sponsored 15 CIPN-directed clinical trials that studied its prevention (alpha lipoic acid, intravenous calcium/magnesium, vitamin E, acetyl-L-carnitine, or glutathione) and symptomatic treatment (nortriptyline, gabapentin, lamotrigine, amifostine, topical amitriptyline/ketamine, topical baclofen,/amitriptyline/ketamine, or duloxetine). Of these studies, only duloxetine was shown to help neuropathic pain in established CIPN."
  • "Many other medications (gabapentin, topical preparations, etc.) are used in an off-label fashion. Novel electrostimulation techniques have shown early promise but benefits need to be confirmed in ongoing larger randomized and controlled trials."
Quotes
  • "Currently, there is no approved therapy for the treatment of CIPN. The current therapeutic landscape of CIPN worldwide is dependent on off-label therapies, used to reduce the symptoms in CIPN patients."
Quotes
  • "Duloxetine belongs to a class of drugs called serotonin-norepinephrine reuptake inhibitors (SNRIs)."
  • "Duloxetine oral capsule is used to treat anxiety, depression, diabetes nerve pain, fibromyalgia, and chronic muscle and joint pain."
Quotes
  • "A total of 26 treatment options in 35 studies were identified. "
  • "The evidence is considered of moderate benefit for duloxetine. Photobiomodulation, known as low level laser therapy, is considered of moderate benefit based on the evidence review. Evidence did not support the use of lamotrigine and topical KA (4% ketamine and 2% amitriptyline). "
  • "The evidence for tricyclic antidepressants was inconclusive as amitriptyline showed no benefit but nortriptyline had insufficient evidence. Further research on CIPN treatment is needed with larger sample sizes, long-term follow-up, standardized outcome measurements, and standardized treatment timing. "