Transcript Oxaliplatin Induced Sensory Neuropathy

Oxaliplatin Induced
Sensory Neuropathy
Sandra E. Kurtin, RN, MS, AOCN®, ANP-C
Clinical Assistant Professor of Medicine
Adjunct Clinical Assistant Professor of Nursing
Nurse Practitioner
The University of Arizona Cancer Center
Chemotherapy-Induced Peripheral
Neuropathy (CIPN)
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31 pairs of nerves carry impulses to
and from the spinal cord (spinal
nerves)
Each spinal nerve has
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These merge with fibers outside the
cord to form peripheral nerves with
corresponding dermatomes
CIPN:
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Netter, 1993; Stubblefield et al, 2009 - JNCCN.
Anterior (ventral) root = motor
Posterior (dorsal) root = sensory
Most often symmetrical, distal, length
dependent
Predominantly sensory
Chemotherapy-Induced Neurotoxicity
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Peripheral nerves
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Motor axons (nerve fibers) = large, myelinated
Sensory and autonomic axons = small, unmyelinated or thinly myelinated
Most neurotoxic drugs cause axonal damage
Small fibers are affected early and most frequently
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Limited capacity for repair
Most located in the DRG
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Outside the blood-brain barrier
Highly permeable to toxic compounds
Autonomic nerves are less sensitive to neurotoxic chemotherapy
DRG = dorsal root ganglion.
Stubblefield et al, 2009, JNCCN
Pathogenesis and Associated Morphological
Changes in CIPN
Han & Smith (2013) Frontiers in Pharmacology:, 4:156;1-16
The GSTP1 Gene
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One of the metabolic routes of oxaliplatin involves the conjugation of the
platinum-diaminocyclohexane metabolite to glutathione.
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GSTP1
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widely expressed in normal human epithelial tissues a
highly overexpressed in colon cancer
plays a part in the detoxification of platinum drugs
GSTP1 Ile105Val SNP (A SNP (A313G) in exon 5 of the GSTP1 gene)
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catalyzed by the enzyme glutathione S-transferase (GST), a multigene family of
enzymes that are cytosolic and membrane-bound.
significantly decreases GSTP1 activity
Asian populations have a lower prevalence of the I105V polymorphism in the
GSTP1 gene
23 studies exploring the possible connection between the peripheral
neurotoxicity of platinum and the GSTP1 Ile105Val SNP (rs1695;
NP_000843.1)
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10 of these studies, a correlation between this SNP and platinum-induced
neurotoxicity was reported
13 studies with no correlation
Zedan et al, (2013) Clinical Colorectal Cancer,
Characteristics of CIPN
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Sensory Symptoms
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Paresthesia
Hyperesthesia/hypoesthesia
Dysesthesia
Pain
Numbness and tingling
Hyporeflexia or areflexia
Diminished or no proprioception
Diminished or absent vibratory or
cutaneous sensation
Diminished or absent sense of
discrimination between sharp and
dull
Visovsky et al, 2007; Wickham, 2007.
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Motor Symptoms
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Weakness
Gait disturbance
Balance disturbance
Difficulty with fine motor skills
Autonomic Symptoms
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Constipation
Urinary retention
Sexual dysfunction
Blood pressure alterations
Predisposing Factors
General Considerations
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Endocrine disorders
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Disease- and Treatment-Related
Factors
Hypothyroidism
Diabetes
Nutritional disease
Connective tissue disease
Vascular disease
Anemia
Hypoalbuminemia
Alcohol consumption
Hypomagnesemia
Medications
Herpes zoster
Polymorphisms in glutathione
transferase pathway (GSTP1)
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Nerve root compression from
bulky abdominal/pelvic disease
Lymphedema
Post-surgical nerve damage
Oxaliplatin Regimens:
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Treatment schedule
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Cumulative dose
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Time of infusion
Wickham, 2007; Hausheer et al, 2006; Gleason et al, 2010; Stubblefield et al, 2009; Lockwood-Rayermann, 2007; Sereno et al, 2014
Oxaliplatin-Induced
Peripheral Neuropathy
Transient Acute
Neurotoxicity
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Common (85-90%)
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Dose dependent: (10-15%)
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No coasting effect
Aggravated by exposure to cold
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Paresthesias and or dysethesias
Distal extremities and/or perioral
region
Less Common:
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Onset: 750-850mg/m2
Duration:
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Clinical Findings:
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Onset within minutes of infusion
Duration variable – 4-5 days average
Improvement between cycles
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Cumulative neuropathy
Pharyngolaryngeal dysethesias
Tetanic spasms
Fasiculations
Prolonged muscle contractions
Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178
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Symptoms may persist between cycles
and increase in intensity with continued
exposure
Severity may increase even after stopping
the drug (coasting)
Majority may recover to <grade 1 within
6-12 months
May be irreversible and limit ADLS if
severe
Clinical Findings:
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Dysesthesias and paresthesias
Sensory loss
Distal extremities
Non-cold related symptoms
Incidence of Oxaliplatin-Induced Neuropathy
(OXLIN)
Regimen
Tumor Type
Frequency and severity
MOSAIC Trial
Colorectal
44% grade 2-3
European Trial
Colorectal
26% grade 3 persisting beyond 28 months
NSABP C-07 trial
Colorectal
>10% with persistent symptoms at 2 years
Cassidy et al
(FOLFOX vs XELOX)
Colorectal
80% all grades, 17% grade > 3
Argyrou et al
(FOLFOX 4 vs. XELOX
Colorectal
OXLIN more common in FOLFOX4 despite
similar cumulative doses
De Gramont et al
(OPTIMOX)
Colorectal
13% vs 19% grade 3 (p=0.0017) favoring the
stop and go with equivalent RR (63.1 vs 59.8%)
and PFS (9.2 vs 8.9 months)
Yang et al
(XELOC vs CAPOX)
Gastric
64% (all grades) , no difference between
regimens
Li et al (GEMOX)
Pancreatobiliary
3% grade 3
GERCOR
(S-GEMOX vs. GEMOX)
Pancreatic
GEMOX – 0% grade 3
S-GEMOX – 21% grade 3
Overman et al (CAPOX)
Small bowel
10% grade 2-3
Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178
The Challenges in Evaluating
Peripheral Neuropathy
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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
Neuropathic symptoms such as pain and paresthesia
are predominantly subjective with variable thresholds
for tolerance
Cleeland et al, 2010; Hausheer et al, 2006.
Select Neurotoxicity Grading Scales
Scale
Category
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
ECOG
Motor
Subjective
weakness; no
objective findings
Mild objective weakness
without significant
impairment of function
Objective weakness
with impairment of
function
Paralysis
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Sensory
Mild parathesias;
loss of DTR
Mild or moderate
objective sensory loss;
moderate paresthesias
Severe objective
sensory loss or
paresthesias that
interfere with function
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Neuropathy
motor
Asymptomatic;
clinical or diagnostic
observations only;
intervention not
indicated
Moderate symptoms;
limiting instrumental
ADL
Severe symptoms;
limiting self care ADL;
assistive device
indicated
Life-threatening
consequences;
urgent
intervention
indicated
Death
Neuropathy
sensory
Asymptomatic; loss
of DTRs or
paresthesia
Moderate symptoms;
limiting instrumental
ADL
Severe symptoms;
limiting self care ADL
None
Paresthesia
and/or decreased
DTR
Severe paresthesias
and/or mild weakness
Intolerable paresthesia
and/or motor loss
NCI-CTC
v.4.0
WHO
Toxicity
Criteria
Adapted from Paice, 2009.
Life-threatening
consequences;
urgent
intervention
indicated
Paralysis
Death
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Assessment of CIPN
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Baseline assessment of PN symptoms prior to the
initiation of cancer therapy
Identify individuals at risk for severe neuropathy
Ongoing assessment of CIPN is recommended as
chemotherapy treatment progresses
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Awareness of onset dose for individual agents
Treatment delays or dose modifications due to CIPN
Consistent documentation/communication among
providers and care-givers
Aring et al, 2005; Hausheer et al, 2006; Wickham, 2007, Stubblefield et al, 2009.
Assessment of Sensory CIPN
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Subjective assessment: Symptoms related to PN
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Pain, numbness, burning, tingling, paresthesias, Lhermitte’s sign, and
autonomic signs
Objective assessment: Physical exam
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Touch, perception of sharp/dull
Vibration
Gait and balance – proprioception
Reflexes
Muscle strength
Shy et al, 2003; Cavaletti et al, 2003; Stubblefield et al, 2009 ; Wickham et al, 2007; Malik et al, 2008.
Neuropathy Assessment Tool
Not at
all
A little
bit
Somewhat
Quite a bit
Very
much
I have numbness or tingling in my hands
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1
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3
4
I have numbness or tingling in my feet
0
1
2
3
4
I feel discomfort in my hands
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1
2
3
4
I feel discomfort in my feet
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1
2
3
4
I have joint pain or muscle cramps
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1
2
3
4
I feel weak all over
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1
2
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I have trouble hearing
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1
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4
I get a ringing or buzzing in my ears
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1
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4
I have trouble buttoning buttons
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I have trouble feeling the shape of small
objects when they are in my hand
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I have trouble walking
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4
Cella et al, 2003; Tariman et al, 2008.
Management of Oxaliplatin Induced
Peripheral Neuropathy
Clinical Management
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Accurate baseline and ongoing
assessment
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Patient Education
Supplements, gabapentin, tricyclic
antidepressants, or other agents may
be helpful in relieving neuropathic
pain
Wickham, 2007; Visovsky et al, 2007; Argyriou et al, 2008. Hausheer et al, 2006.
Safety
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Consistent documentation and
communication
Consider modification of infusion
time, dose reduction,
and treatment holidays
Focus physical assessment on
symptoms
Pharmacologic interventions
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Referral for assistive devices to
maintain ADL and prevent
injuries from falls
Self-care strategies
Symptom reporting
Consider adjunct therapies and
monitor effectiveness
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Massage, acupuncture, cognitive
behavioral therapy, stress reduction
General Approach to Minimize the Burden of
Oxaliplatin-Induced Peripheral Neuropathy
Setting
Aim
Measure
Metastatic
Prevention
Stop-and-Go approach
Calcium and Magnesium Infusions
Treatment
Temporary interruption of oxaliplatin
Neuroprotective agents
Prevention
Calcium and Magnesium Infusions
Treatment
Dose- reduction
Omit Oxaliplatin in alternating cycles
Neuroprotective agents
Adjuvant
Hoff et al, (2012) Clinical Colorectal Cancer, 11:2;93-100
Pharmacological Management of Neuropathic Pain
Agent
Dosing and Clinical Management
Duloxetine
Dosing: 20–30 mg starting dose; no evidence that higher doses are more
effective; 2 week trial for evaluation
Potential AE: Nausea, xerostomia, constipation, diarrhea
Gabapentin
Dosing: 100–300 mg qd–tid; max dose 3,600 mg/day; 1–2 weeks at MTD
is sufficient for evaluation
Potential AE: Somnolence, dizziness, edema, cognitive impairment
5% Lidocaine
patch
Dosing: Maximum of 3 patches daily; 2 week trial for evaluation
Potential AE: Rash erythema
Opioids
Variable dosing by agent; 4–6 week trial for evaluation with dose titration
Potential AE: Constipation, nausea, sedation, confusion, respiratory
Pregabalin
Dosing: 25–50 mg tid; max dose 200 mg tid; period for evaluation unclear
Potential AE: Dizziness, somnolence, xerostomia, edema, blurred vision,
decreased concentration
Tramadol
Dosing: 50 mg 1–2/day; max dose 400 mg/day; 4 week trial for evaluation
Potential AE: Dizziness, constipation, nausea, somnolence, orthostatic
hypotension, increased risk of seizures, serotonin syndrome
Tricyclic
antidepressants
Dosing: Variable dosing by agent; 6–8 week trial for evaluation
Potential AE: Cardiovascular disease, anticholinergic effects, CYP450
Stubblefield et al, 2009, JNCCN.
Common Supplements Used to Treat
Peripheral Neuropathy
Vitamin/Supplement
Dosing Regimen
Multi-B complex vitamins (with B1,
B6, B12, folic acid, and others)
B6 should be approximately 50 mg daily, not to exceed 100 mg per day
Folic acid should be 1 mg per day
Vitamin E
400 IU daily
Vitamin D
400–800 IU daily
Fish oils (omega-3 fatty acids [EPA
and DHA])
1–2 capsules daily with food (1 capsule is usually 1 g)
Magnesium
Suggested dose 250 mg twice a day
May cause diarrhea in larger doses
Potassium
Either as provided by the treating physician or foods rich in potassium
(eg, bananas, oranges, potatoes)
Tonic water (Seltzer water)
Drink 1 glass in evening and any other time cramping occurs
Acetyl-L-carnitine
500 mg twice a day with food
Can take up to 2,000 mg a day
Alpha-lipoic acid
300 mg to 1,000 mg a day with food
Glutamine
1 g up to 3 times a day with food
Goshajinkigan (GJG)
Kampo – Japanese Herb
Richardson et al, 2010.
Meta-Analysis Calcium/Magnesium
Infusions
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Seven Trials:
 Four prospective randomized clinical trials
 Three retrospective clinical trials
 1170 colorectal cancer patients
 802 received Ca/Mg infusions (Ca/Mg group)
 368 did not receive Ca/Mg infusions ((control group).
Incidence of CTC-AE grade3 acute neurotoxicity:
 significantly lower in the Ca/Mg group compared to the control group
(OR = 0.26; 95% confidence interval (CI), 0.11 to 0.62; P = 0.0002).
Total rate of cumulative neurotoxicity, and that of grade 3 in particular,
 significantly lower in the Ca/Mg group than in the control group
(OR = 0.42; 95% CI 0.26–0.65; P = 0.0001; OR = 0.60; 95% CI 0.39–
0.92; P = 0.02, respectively).
Wen et al (2013) Annal s of Oncology, 24:171-178
Meta-Analysis Calcium/Magnesium
Infusions
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Total doses and cycles of oxaliplatin
 Ca/Mg (MD = 246.73 mg/m2; 95% CI 3.01– 490.45; P = 0.05)
 Control group (MD = 1.55; 95% CI 0.46–2.63; P = 0.005)
No significant differences in treatment efficacy:
 PFS (MD = 0.71 month; 95% CI −0.59–2.01; P = 0.29)
 Median OS (MD = 0.10 month; 95% CI −0.41–0.61; P = 0.70)
 RRs (OR = 0.82; 95% CI 0.61–1.10; P = 0.18)
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Loprinzi et al, 2013 - JCO
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Randomized phase III study comparing placebo plus Oxaliplatin based
regimen vs CaMg infusion in 353 pts with colon cancer
CaMg did not reduce cumulative OXLIN
Wen et al (2013) Annal s of Oncology, 24:171-178
Impact of oxaliplatin-induced neuropathy:
a patient perspective
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Twenty patients were
assessed, 12.6±2.8 months
after treatment cessation
 mean cumulative
oxaliplatin dose, 789
mg/m2
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Neurotoxicity
necessitated early
cessation of treatment in
40% of patients.
Mild
Moderate
Severe
• Discrepancy in grading of severity of OXLIN between patients and clinicians
• Providers: 10% with severe OXLIN
• Patient self-report: 60% with severe OXLIPN with significant physical limitations
due to neuropathic symptoms
• The majority (85%) of patients had objective evidence of sensory neuropathy with
nerve conduction studies.
Bennett et al (2012) Support Care Cancer, 20:2959–2967
Key Takeaways
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Oxaliplatin induced neurotoxicity remains a clinical challenge
More well-designed, sufficiently powered trials specifically on
patients with CIPN are necessary
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Validation of evaluation tools
Combinations and sequence of prevention and treatment
strategies
Further characterization of the GPTS1 and other SNPs may
offer insight into patients at greater risk for toxicity
Clinical assessment at baseline and throughout therapy is
critical to identification of patients at risk and those developing
more severe OXLIN to allow for early intervention
Patient reported outcomes and involvement of caregivers is
imperative
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Hausheer et al, 2006; Wickham, 2007.