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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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Oxaliplatin Induced Sensory Neuropathy

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  1. Oxaliplatin Induced Sensory Neuropathy Sandra E. Kurtin, RN, MS, AOCN®, ANP-C Clinical Assistant Professor of Medicine Adjunct Clinical Assistant Professor of NursingNurse Practitioner The University of Arizona Cancer Center

  2. 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 Netter, 1993; Stubblefield et al, 2009 - JNCCN.

  3. 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

  4. Pathogenesis and Associated Morphological Changes in CIPN Han & Smith (2013) Frontiers in Pharmacology:, 4:156;1-16

  5. 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,

  6. 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.

  7. Predisposing Factors General 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

  8. Oxaliplatin-Induced Peripheral Neuropathy Transient Acute Neurotoxicity Cumulative 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

  9. Incidence of Oxaliplatin-Induced Neuropathy (OXLIN) Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178

  10. 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.

  11. Select Neurotoxicity Grading Scales Adapted from Paice, 2009.

  12. 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.

  13. 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.

  14. Neuropathy Assessment Tool Cella et al, 2003; Tariman et al, 2008.

  15. 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.

  16. General Approach to Minimize the Burden of Oxaliplatin-Induced Peripheral Neuropathy Hoff et al, (2012) Clinical Colorectal Cancer, 11:2;93-100

  17. Pharmacological Management of Neuropathic Pain Stubblefield et al, 2009, JNCCN.

  18. 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 Common Supplements Used to Treat Peripheral Neuropathy Goshajinkigan (GJG) Kampo – Japanese Herb Richardson et al, 2010.

  19. 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

  20. 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 OXLIN Wen et al (2013) Annal s of Oncology, 24:171-178

  21. 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. 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

  22. 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.

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