Audio and slides for this presentation are available on YouTube: http://youtu.be/dYRu8PVLU14 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.

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. Topics of Discussion
•What is chemotherapy induced
peripheral neuropathy (CIPN)?
•What are the risk factors?
•What can we do about it?

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. •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. 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. • 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. 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. Functional
Disability
Loss of
Sensation
Peripheral
Neuropathy
Exaggerated
Sensation

9. Walking
Driving
Hobbies
Picking up
things
Relation-
ships
Chores
WorkWriting
Exercise
Sleep
Sexual
Activity

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. 1) Prevent it
2) Recognize it early
3) Control the pain
4) Minimize effects on quality of life

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. • 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. • 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. 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. • 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. 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. Cycle Number
Perceived Loss
of Balance
Fall Risk

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?

21. Controlling
Neuropathic Pain
Neuropathic pain is
severe, difficult to
treat, and may not
respond well to
narcotic analgesics.
Image retrieved from http://www.topnews.in/health/files/chronic-pain.jpg

22. Describing Your Pain
•Onset
•Location
•Duration
•Characteristics
•Aggravating Factors
•Relieving Factors
•Treatments tried

23. 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)

24. •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

25. 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

26. 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

27. • 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)

29. 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).

30. 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).

31. 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).

32. 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

33. 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)

34. • 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).

35. • Neurologist to establish/confirm diagnosis
• Pain management
• Physiatrist-physician who specialize in cancer rehabilitation, locate
one at http://www.cancer.net/survivorship/rehabilitation
• 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)

37. 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.