Download - Oxaliplatin Induced Sensory Neuropathy
Oxaliplatin Induced Sensory Neuropathy
Sandra E. Kurtin, RN, MS, AOCN®, ANP-CClinical Assistant Professor of Medicine
Adjunct Clinical Assistant Professor of NursingNurse Practitioner
The University of Arizona Cancer Center
Netter, 1993; Stubblefield et al, 2009 - JNCCN.
Chemotherapy-Induced Peripheral Neuropathy (CIPN)
31 pairs of nerves carry impulses to and from the spinal cord (spinal nerves)
Each spinal nerve has Anterior (ventral) root =
motor Posterior (dorsal) root =
sensory These merge with fibers
outside the cord to form peripheral nerves with corresponding dermatomes
CIPN: Most often symmetrical,
distal, length dependent Predominantly sensory
Chemotherapy-Induced Neurotoxicity Peripheral nerves
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 Limited capacity for repair Most located in the DRG
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 One of the metabolic routes of oxaliplatin involves the
conjugation of the platinum-diaminocyclohexane metabolite to glutathione. catalyzed by the enzyme glutathione S-transferase (GST), a
multigene family of enzymes that are cytosolic and membrane-bound.
GSTP1 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) 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) 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
Sensory Symptoms 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
Motor Symptoms Weakness Gait disturbance Balance disturbance Difficulty with fine motor
skills Autonomic
Symptoms Constipation Urinary retention Sexual dysfunction Blood pressure alterations
Visovsky et al, 2007; Wickham, 2007.
Predisposing FactorsGeneral Considerations Disease- and Treatment-
Related Factors Endocrine disorders
Hypothyroidism Diabetes
Nutritional disease Connective tissue disease Vascular disease Anemia Hypoalbuminemia Alcohol consumption Hypomagnesemia Medications Herpes zoster Polymorphisms in glutathione
transferase pathway (GSTP1)
Nerve root compression from bulky abdominal/pelvic disease
Lymphedema Post-surgical nerve damage Oxaliplatin Regimens:
Treatment schedule Cumulative dose 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 NeurotoxicityCumulative neuropathy
Common (85-90%) Onset within minutes of infusion Duration variable – 4-5 days average Improvement between cycles
No coasting effect Aggravated by exposure to cold
Clinical Findings: Paresthesias and or dysethesias Distal extremities and/or perioral
region Less Common:
Pharyngolaryngeal dysethesias Tetanic spasms Fasiculations Prolonged muscle contractions
Dose dependent: (10-15%) Onset: 750-850mg/m2 Duration:
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: Dysesthesias and paresthesias Sensory loss Distal extremities Non-cold related symptoms
Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178
Incidence of Oxaliplatin-Induced Neuropathy (OXLIN) Regimen Tumor Type Frequency and severityMOSAIC Trial Colorectal 44% grade 2-3European Trial Colorectal 26% grade 3 persisting beyond 28
monthsNSABP C-07 trial Colorectal >10% with persistent symptoms at 2
yearsCassidy 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 3S-GEMOX – 21% grade 3
Overman et al (CAPOX)
Small bowel 10% grade 2-3Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178
The Challenges in Evaluating Peripheral Neuropathy
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.
Scale Category Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
ECOG Motor
Sensory
Subjective weakness; no
objective findings
Mild parathesias; loss of DTR
Mild objective weakness without significant
impairment of function
Mild or moderate objective sensory loss; moderate paresthesias
Objective weakness with impairment of
function
Severe objective sensory loss or
paresthesias that interfere with function
Paralysis
–
–
–
NCI-CTC v.4.0
Neuropathymotor
Neuropathysensory
Asymptomatic; clinical or diagnostic observations only;
intervention not indicated
Asymptomatic; loss of DTRs or paresthesia
Moderate symptoms; limiting instrumental ADL
Moderate symptoms; limiting instrumental ADL
Severe symptoms; limiting self care ADL;
assistive device indicated
Severe symptoms; limiting self care ADL
Life-threatening consequences;
urgent intervention
indicated
Life-threatening consequences;
urgent intervention
indicated
Death
Death
WHOToxicity Criteria
None Paresthesiaand/or decreased
DTR
Severe paresthesias and/or mild weakness
Intolerable paresthesia and/or motor loss
Paralysis –
Adapted from Paice, 2009.
Select Neurotoxicity Grading Scales
Assessment of CIPN 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 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
Subjective assessment: Symptoms related to PN Pain, numbness, burning, tingling, paresthesias,
Lhermitte’s sign, and autonomic signs Objective assessment: Physical exam
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
muchI have numbness or tingling in my hands 0 1 2 3 4
I have numbness or tingling in my feet 0 1 2 3 4
I feel discomfort in my hands 0 1 2 3 4
I feel discomfort in my feet 0 1 2 3 4
I have joint pain or muscle cramps 0 1 2 3 4
I feel weak all over 0 1 2 3 4
I have trouble hearing 0 1 2 3 4
I get a ringing or buzzing in my ears 0 1 2 3 4
I have trouble buttoning buttons 0 1 2 3 4
I have trouble feeling the shape of small objects when they are in my hand
0 1 2 3 4
I have trouble walking 0 1 2 3 4
Cella et al, 2003; Tariman et al, 2008.
Management of Oxaliplatin Induced Peripheral Neuropathy
Clinical Management Patient Education Accurate baseline and ongoing
assessment Consistent documentation and
communication Consider modification of
infusion time, dose reduction, and treatment holidays
Focus physical assessment on symptoms
Pharmacologic interventions Supplements, gabapentin,
tricyclic antidepressants, or other agents may be helpful in relieving neuropathic pain
Safety Referral for assistive devices
to maintain ADL and prevent injuries from falls
Self-care strategies Symptom reporting
Consider adjunct therapies and monitor effectiveness Massage, acupuncture,
cognitive behavioral therapy, stress reduction
Wickham, 2007; Visovsky et al, 2007; Argyriou et al, 2008. Hausheer et al, 2006.
General Approach to Minimize the Burden of Oxaliplatin-Induced Peripheral NeuropathySetting Aim MeasureMetastatic Prevention Stop-and-Go approach
Calcium and Magnesium InfusionsTreatment Temporary interruption of oxaliplatin
Neuroprotective agentsAdjuvant Prevention Calcium and Magnesium Infusions
Treatment Dose- reductionOmit Oxaliplatin in alternating cyclesNeuroprotective agents
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 evaluationPotential 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 evaluationPotential AE: Somnolence, dizziness, edema, cognitive impairment
5% Lidocaine patch
Dosing: Maximum of 3 patches daily; 2 week trial for evaluationPotential AE: Rash erythema
Opioids Variable dosing by agent; 4–6 week trial for evaluation with dose titrationPotential AE: Constipation, nausea, sedation, confusion, respiratory
Pregabalin Dosing: 25–50 mg tid; max dose 200 mg tid; period for evaluation unclearPotential 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 evaluationPotential 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 evaluationPotential AE: Cardiovascular disease, anticholinergic effects, CYP450
Stubblefield et al, 2009, JNCCN.
Common Supplements Used to Treat Peripheral Neuropathy
Dosing RegimenVitamin/Supplement
1 g up to 3 times a day with foodGlutamine
300 mg to 1,000 mg a day with foodAlpha-lipoic acid
500 mg twice a day with foodCan take up to 2,000 mg a day
Acetyl-L-carnitine
Drink 1 glass in evening and any other time cramping occursTonic water (Seltzer water)
Either as provided by the treating physician or foods rich in potassium (eg, bananas, oranges, potatoes)
Potassium
Suggested dose 250 mg twice a dayMay cause diarrhea in larger doses
Magnesium
1–2 capsules daily with food (1 capsule is usually 1 g)Fish oils (omega-3 fatty acids [EPA and DHA])
400–800 IU dailyVitamin D
400 IU dailyVitamin E
B6 should be approximately 50 mg daily, not to exceed 100 mg per dayFolic acid should be 1 mg per day
Multi-B complex vitamins (with B1, B6, B12, folic acid, and others)
Richardson et al, 2010.
Goshajinkigan (GJG) Kampo – Japanese Herb
Meta-Analysis Calcium/Magnesium Infusions 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 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)
Loprinzi et al, 2013 - JCO Randomized phase III study comparing placebo plus
Oxaliplatin based regimen vs CaMg infusion in 353 pts with colon cancer
CaMg did not reduce cumulative OXLINWen et al (2013) Annal s of Oncology, 24:171-178
Impact of oxaliplatin-induced neuropathy:a patient perspective
Twenty patients were assessed, 12.6±2.8 months after treatment cessation mean cumulative
oxaliplatin dose, 789 mg/m2
Neurotoxicity necessitated early cessation of treatment in 40% of patients.
Bennett et al (2012) Support Care Cancer, 20:2959–2967
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.
Key Takeaways Oxaliplatin induced neurotoxicity remains a clinical challenge More well-designed, sufficiently powered trials specifically on
patients with CIPN are necessary 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
Hausheer et al, 2006; Wickham, 2007.