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.