Chemotherapy Related Neuropathy: Managing this Nerve Wracking Problem


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Cindy Tofthagen, PhD, ARNP, an assistant professor of nursing at the University of South Florida in Tampa and a post-doctoral fellow at the University of Massachusetts and Dana-Farber Cancer Institute, talks about chemotherapy-induced peripheral neuropathy (CIPN), the risk factors of CIPN, and how to manage the condition. This presentation was originally given at Dana-Farber Cancer Institute on Aug. 6, 2013 and put on by Dana-Farber's Blum Resource Center.

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  • Read slide.A review of the literature resulted in identification of 3 existing self-report tools for CIPN.
  • A hypothesized mechanism for both taxane and platinum based neurotoxicity is the result of oxidative stress (Joseph, Chen, Bogen, & Levine, 2008; Mir et al., 2009). Accumulation of platinum within the dorsal root ganglia may decreased cellular metabolism and axoplasmatic transport in patients treated with platinum based chemotherapy (Argyriou, Polychronopoulos, Iconomou, Chroni, & Kalofonos, 2008; Milla et al., 2009). Paclitaxel induces a rapid decline in axonal mitochondrial membrane potential, spontaneous neuronal firing, and reactive oxygen species production, resulting in functionally impaired, swollen, and vacuolated axonal mitochondria in both unmyelinated and myelinated axons (Flatters & Bennett, 2006; Siau & Bennett, 2006; Wei, Flatters, Xiao, Mulhern, & Bennett, 2008).  Oxidative stress may induce an NF-kappa B inflammatory cascade in persons with peripheral neuropathy, resulting in increased levels of inflammatory cytokines (Kuhad & Chopra, 2009; Kumar & Sharma, 2010). Laboratory studies indicate that Elevated levels of inflammatory cytokines including (Cox 2, TNF-alpha, IL-1beta, TGF-1beta) have been associated with increased neuropathic symptoms in diabetic rats (Kuhad & Chopra, 2009; Kumar & Sharma, 2010; Negi, Kumar, & Sharma, 2011).
  • Preventative strategies have been the primary focus of research to date but have so far failed to provide effective methods to prevent it.Prevention may differ depending on neurotoxic agents the patient is receiving.Target underlying mechanisms behind CIPN, which are not well understood.
  • More research still needed because of small sample sizes in each study.
  • To measure side-effects associated with cancer treatments, large scale clinical trials often use grading scales, such as the National Cancer Institute’s (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), WHO and ECOG scales.These criteria have been used to establish cut points for treatment toxicity, delays and/or reductions, rather than as comprehensive measures of the patient’s symptom experience. There are no guidelines for training of evaluators, no standardization of agreement as to what constitutes some subjective assessment of “weakness interfering with function”, ensuring wide variation ion scoring for the same patient presentation.In general, grading scales lack the sensitivity needed to capture the full impact of CIPN.
  • Fall risk increases with each cycle of chemotherapy
  • NP is often described as burning, shooting, stabbing, electric like, or pins and needles. An aggressive approach to pain management should be taken and may involve use of several different classes of medications.Pain is whatever the person says it is, experienced whenever the person says it is.
  • Requires aggressive treatment approach and frequent communication with the patientCaution: Even though these guidelines have been developed by experts and are evidence based, they may be of limited benefit for CIPN.A combination approach will probably be required.Add additional agents sequentially if partial but inadequate pain relief
  • These techniques may provide symptomatic relief ofnumbness and tingling for patients with CIPN with minimal foreseeable risks.
  • Allet and colleagues (2010) reported significantly improved balance and strength, increased walking speed, and decreased fear of falling in participants a 60 minute, twice a week for 12 weeks, strength, balance, and functional training program. The results were sustained for a period of six months. Furthermore, the training program was feasible and safe for persons with peripheral neuropathy.
  • Chemotherapy Related Neuropathy: Managing this Nerve Wracking Problem

    1. 1. Chemotherapy Related Neuropathy: Managing this Nerve Wracking Problem Cindy Tofthagen, PhD, ARNP, AOCNP, FAANP University of South Florida University of Massachusetts Boston/Dana-Farber Cancer Institute
    2. 2. Topics of Discussion •What is chemotherapy induced peripheral neuropathy (CIPN)? •What are the risk factors? •What can we do about it?
    3. 3. What is CIPN? A group of neuromuscular symptoms that result from nerve damage caused by drug therapies used in the treatment of cancer. Affects 30-100% of patients getting specific neurotoxic chemotherapy drugs. The most commonly used classes of drugs causing peripheral neuropathy are taxanes (Taxol and Taxotere) and platinum based drugs (cisplatin and oxaliplatin).
    4. 4. •Sensory, motor, or autonomic •Vary from person to person based on type of treatment and individual differences •Numbness, tingling, and discomfort in the upper or lower extremities are the hallmarks of peripheral neuropathy Symptoms
    5. 5. Problem CIPN can last for months to years after chemotherapy and sometimes is permanent. It can interfere with the ability to perform usual activities.
    6. 6. • Increasing dose • Pretreatment or concurrent treatment with other neurotoxic chemotherapies • Diabetes • Hypothyroidism • HIV infection • Charcot-Marie-Tooth disease • Autoimmune disorders • Vitamin B12 deficiency • Chronic alcohol abuse • Shingles
    7. 7. Supposedly chemotherapy increased my chances of living 5 years by 8%. I don’t want to live for another 5 years like this. My hands and fingers are numb. My feet are numb. My legs are numb from my knees to the bottom of my feet. I have pain, gnawing, burning, and cramping most of the time. My legs ache and feel stiff and heavy all the time. Driving is a problem, walking is a problem, Being on my feet is a problem. My hands don’t work. I feel collapsed, dizzy, and weak all day, every day, all the time. I have disabling fatigue. I feel like I have been poisoned. -written in 2008 by Sue, colorectal cancer survivor. (Tofthagen, 2010)
    8. 8. Functional Disability Loss of Sensation Peripheral Neuropathy Exaggerated Sensation
    9. 9. Walking Driving Hobbies Picking up things Relation- ships Chores WorkWriting Exercise Sleep Sexual Activity
    10. 10. Possible Mechanisms • Oxidative stress • Demyelination • Cytokine mediated inflammation • Sodium ion channel dysfunction • Damage to dorsal root ganglion • Combinations of these • May vary by drug • Genetic factors may influence
    11. 11. 1) Prevent it 2) Recognize it early 3) Control the pain 4) Minimize effects on quality of life
    12. 12. A variety of preventative strategies have been evaluated thus far with varying degrees of success, including:  Calcium/Magnesium Infusions Alpha-lipoic acid B Vitamins Glutamine/glutathione Vitamin E
    13. 13. • Numerous clinical trials supporting its use • One trial was closed because of safety concerns • Recent meta-analysis confirmed safety and efficacy of Calcium and Magnesium infusions for prevention of neuropathy caused by oxaliplatin only • Reduces the incidence of grade 2 but not grade 1 neuropathy (Grothey et al., 2011; Hochster, Grothey, & Childs, 2007; Ishibashi, Okada, Miyazaki, Sano, & Ishida, 2010; Wen et al., 2012)
    14. 14. • Neurotoxicity may be directly related to individual variations in neurotoxic drug metabolism, distribution, and elimination. • Genetic polymorphisms associated with CIPN may lead to genetic tests to help identify individuals likely to develop severe neuropathy Bergmann, et al., 2011; Sissung, et al., 2006; Renbarger, et. al., 2008; Hertz, et al., 2012; Kroetz, et al., 2010; Schneider, et al., 2011.
    15. 15. Caucasians (n = 92) African- Americans (n = 22) P-value Male:Female 46:46 12:10 .81 Cumulative vincristine dose 52 14.4 47.1 13 0.15 Experienced vincristine- related neurotoxicity (%) 32/92 (34.8%) 1/22 (4.5%) 0.004 Doses omitted due to vincristine-related neurotoxicity (%) 40/2559 (1.6%) 1/691 (0.1%) 0.0009 Doses reduced due to vincristine-related neurotoxicity (%) 127/2559 (5%) 1/691 (0.1%) <0.0001 Renbarger, et al., Pediatric Blood Cancer, 2007.
    16. 16. • Diagnosing and grading of PN is not straightforward • Many different grading scales are available, but no standard method for administering or interpreting these scales has been developed • Available grading scales have many limitations
    17. 17. Nurse’s Self-Assessment of Skills and Practices • 82% recognize CIPN as a significant problem • 75% rate own assessment skills as fair to poor Binner,Ross, & Browner, 2011
    18. 18. Cycle Number Perceived Loss of Balance Fall Risk
    19. 19. What to tell your healthcare team 1. What symptoms are you having? 2. Are the symptoms on one or both sides? 3. How much of the extremity is involved? 4. How severe and distressing is each symptom? 5. Are symptoms constant or do they come and go? 6. How are your activities and lifestyle being affected?
    20. 20. Controlling Neuropathic Pain Neuropathic pain is severe, difficult to treat, and may not respond well to narcotic analgesics. Image retrieved from
    21. 21. Describing Your Pain •Onset •Location •Duration •Characteristics •Aggravating Factors •Relieving Factors •Treatments tried
    22. 22. R A N D O M I Z A T I O N T A P E R / W A S H O U T T A P E R / W A S H O U T Duloxetine 30mg daily 1 Capsule Duloxetine 60mg daily 2 Capsules Duloxetine 30mg daily 1 Capsule Duloxetine 60mg daily 2 Capsules Placebo 1 Capsule Placebo 2 Capsules Placebo 1 Capsule Placebo 2 Capsules Taper = 1 capsule daily x 7 days Washout = no capsules for 7 days Stratification Factors: Chemotherapy Class & CIPN Risk Week 1 Weeks 2-5 Weeks 6-7 Week 8 Weeks 13-14Weeks 9-12 CALGB170601:APhaseIIIDoubleBlindTrialofOral DuloxetineforTreatmentofPainfulCIPN Smith, et al., J Clin Oncol 30, 2012 (suppl; abstr CRA9013)
    23. 23. •Based on primary results (n=220) Duloxetine 60mg daily: •Diminishes CIPN pain in the majority •Improves function & QOL •One of the few drugs recommended that has data to support its use for painful CIPN
    24. 24. First Line Tricyclic Antidepressants Gapapentin or Pregabalin Second Line Serotonin-norepinephrine reuptake inhibitors Lidocaine Patch Third Line Tramadol or Controlled Release Opioid Fourth Line Cannabinoids, methadone, lamotrigine, topiramate, valproic acid Moulin, et al., 2007
    25. 25. Drug /Class Starting Dose Titration Maximum Dose Trial Duration Nortriptyline/T CA 25mg at bedtime Increase by 25mg every 3-7 days as tol 150mg/day 6-8 weeks Desipramine/T CA 25mg at bedtime Increase by 25mg every 3-7 days as tol 150mg/day 6-8 weeks Duloxetine/SSN RI 30mg/day Increase to 60mg/day in 7 days 60mg /BID 4 weeks Venlafaxine/SS NRI 37.7mg once or twice a day Increase by 75 mg/week 225mg/day 4-6 weeks Gabapentin 100-300mg TID 100-300mg TID every 1-7 days as tolerated 3600 mg/d (1200 mg 3 times daily) 3-8 wk for Titration and 2 weeks at max dose Pregabalin 50mg TID or 75mg BID Increase to 300mg/day after 3-7 days, then by 150mg/d every 3-7 days 600mg/d 4 weeks Dworkin, et al., 2010
    26. 26. • Pulsed infrared light is delivered to the foot in an effort to improve foot circulation by stimulating nitric acid production • Widely marketed to patients and used by home health agencies • No data to support use for CIPN • No better than sham therapy for diabetic neuropathy (Lavery, Murdoch , Williams , Lavery, 2008)
    27. 27. Treatment of Foot Neuropathy Patients with numbness in the feet should: • wear comfortable, properly fitting shoes • avoid sandals, open toed or open heeled shoes • inspect feet daily for injury • avoid walking barefoot or in socks alone • always check for foreign objects in shoes before putting them on • change shoes in the middle of the day to avoid continued pressure in the same locations (Plummer & Albert, 2008).
    28. 28. Home Safety • Water temperature for bathing should be carefully assesses and the thermostat on the water heater should be adjusted to a maximum of 100 degrees Fahrenheit • run cold water first • use protective gloves when washing dishes • Always use pot holders (Armstrong, Almadrones, & Gilbert, 2005; Hot Water Burns Like Fire Campaign, 2006).
    29. 29. Home Safety • Living areas should be kept well lit • keep walkways clear • nightlights should be kept on in hallways, bathrooms and bedrooms, nonskid mats in the shower or bathtub (Armstrong, Almadrones, & Gilbert, 2005; Visovsky, Collins, Abbott, Aschenbrenner, & Hart, 2007).
    30. 30. Home Safety • store frequently used items in easy-to-reach locations • remove throw rugs and mats • Use sturdy chairs with arm rests • use a long handled reacher to pick up items from the floor • remove clutter around the house • install hand rails in the tub and beside the toilet • use a shower chair and a hand held shower • use hand railing when climbing stairs, • add a strip of brightly colored tape to the steps so that the outline of • each step is clearly visible, • keep walkways and stairs in good repair and free of clutter and debris
    31. 31. Self-Care Techniques • A study of self-reported self care techniques used by patients with related neuropathy (n=450) indicate techniques that patients found helpful in relieving symptoms include: • warm baths (66%) • walking (60%) • massage (41%) • rubbing cream on the feet (47%) • elevating feet (57%) • staying off the feet (59%) • acupuncture (12%) • meditation (20 (Nicholas et al., 2007)
    32. 32. • Compared to healthy people, persons with neuropathy have reduced proprioception, lower extremity sensation, and reduced ankle strength predisposing them to falls • Strength and balance training results in fewer falls • Safe for people with peripheral neuropathy • Tai Chi, a low impact form of Chinese martial art, may help reduce falls and improve balance (Gillespie et al., 2009; Morrison, Colberg, Mariano, Parson, & Vinik, 2010; Allet, et al., 2010; Kruse et al., 2010).
    33. 33. • Neurologist to establish/confirm diagnosis • Pain management • Physiatrist-physician who specialize in cancer rehabilitation, locate one at • Physical therapist -specific exercises designed to help improve muscle strength and balance • Occupational therapists -maintain your independence, adjust to physical limitations • Support groups and mental health professionals • Podiatrists –recommend footwear, and fit for orthotics (Tofthagen, 2012)
    34. 34. Summary • Neuropathy is an uncomfortable and distressing symptom that can interfere with your ability to do the activities you want and need to do on a daily basis. • Scientists are looking for ways to prevent neuropathy caused by chemotherapy. • Patients can get better control of neuropathy symptoms and their effects on quality of life by being aware of treatment options, communicating with their healthcare team and seeking out resources within their community.