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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) 31 pairs of nerves carry impulses to and from the spinal cord (spinal nerves) Each spinal nerve has These merge with fibers outside the cord to form peripheral nerves with corresponding dermatomes CIPN: 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 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. 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) 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) 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 Visovsky et al, 2007; Wickham, 2007. Motor Symptoms Weakness Gait disturbance Balance disturbance Difficulty with fine motor skills Autonomic Symptoms Constipation Urinary retention Sexual dysfunction Blood pressure alterations Predisposing Factors General Considerations Endocrine disorders 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) 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 Neurotoxicity Common (85-90%) Dose dependent: (10-15%) No coasting effect Aggravated by exposure to cold Paresthesias and or dysethesias Distal extremities and/or perioral region Less Common: Onset: 750-850mg/m2 Duration: Clinical Findings: Onset within minutes of infusion Duration variable – 4-5 days average Improvement between cycles Cumulative neuropathy Pharyngolaryngeal dysethesias Tetanic spasms Fasiculations Prolonged muscle contractions Serano et al. (2014) Critical Reviews in Oncology/Hematology,89;166-178 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 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 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 – Sensory Mild parathesias; loss of DTR Mild or moderate objective sensory loss; moderate paresthesias Severe objective sensory loss or paresthesias that interfere with function – – 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 – 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 much I 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 Accurate baseline and ongoing assessment 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 Consistent documentation and communication Consider modification of infusion time, dose reduction, and treatment holidays Focus physical assessment on symptoms Pharmacologic interventions 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 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 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 OXLIN Wen 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. 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 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.