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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.

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Presentation on theme: "Oxaliplatin Induced Sensory Neuropathy Sandra E. Kurtin, RN, MS, AOCN ®, ANP-C Clinical Assistant Professor of Medicine Adjunct Clinical Assistant Professor."— Presentation transcript:

1 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

2 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

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 { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/4245242/14/slides/slide_7.jpg", "name": "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

9 Incidence of Oxaliplatin-Induced Neuropathy (OXLIN) RegimenTumor TypeFrequency and severity MOSAIC TrialColorectal44% grade 2-3 European TrialColorectal26% grade 3 persisting beyond 28 months NSABP C-07 trialColorectal>10% with persistent symptoms at 2 years Cassidy et al (FOLFOX vs XELOX) Colorectal80% all grades, 17% grade > 3 Argyrou et al (FOLFOX 4 vs. XELOX ColorectalOXLIN more common in FOLFOX4 despite similar cumulative doses De Gramont et al (OPTIMOX) Colorectal13% 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) Gastric64% (all grades), no difference between regimens Li et al (GEMOX)Pancreatobiliary3% grade 3 GERCOR (S-GEMOX vs. GEMOX) PancreaticGEMOX – 0% grade 3 S-GEMOX – 21% grade 3 Overman et al (CAPOX)Small bowel10% grade 2-3 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 ScaleCategoryGrade 1Grade 2Grade 3Grade 4Grade 5 ECOGMotor 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 Neuropathy motor Neuropathy sensory Asymptomatic; clinical or diagnostic observations only; intervention not indicated Asymptomatic; loss of DTRs or paresthesia 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 Death WHO Toxicity Criteria NoneParesthesia and/or decreased DTR Severe paresthesias and/or mild weakness Intolerable paresthesia and/or motor loss Paralysis– Adapted from Paice, 2009. Select Neurotoxicity Grading Scales

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 Not at all A little bit SomewhatQuite a bit Very much I have numbness or tingling in my hands01234 I have numbness or tingling in my feet01234 I feel discomfort in my hands01234 I feel discomfort in my feet01234 I have joint pain or muscle cramps01234 I feel weak all over01234 I have trouble hearing01234 I get a ringing or buzzing in my ears01234 I have trouble buttoning buttons01234 I have trouble feeling the shape of small objects when they are in my hand 01234 I have trouble walking01234 Cella et al, 2003; Tariman et al, 2008.

15 Management of Oxaliplatin Induced Peripheral Neuropathy Clinical ManagementPatient 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 SettingAimMeasure MetastaticPreventionStop-and-Go approach Calcium and Magnesium Infusions TreatmentTemporary interruption of oxaliplatin Neuroprotective agents AdjuvantPreventionCalcium and Magnesium Infusions TreatmentDose- reduction Omit Oxaliplatin in alternating cycles Neuroprotective agents Hoff et al, (2012) Clinical Colorectal Cancer, 11:2;93-100

17 Pharmacological Management of Neuropathic Pain AgentDosing and Clinical Management DuloxetineDosing: 20–30 mg starting dose; no evidence that higher doses are more effective; 2 week trial for evaluation Potential AE: Nausea, xerostomia, constipation, diarrhea GabapentinDosing: 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 OpioidsVariable dosing by agent; 4–6 week trial for evaluation with dose titration Potential AE: Constipation, nausea, sedation, confusion, respiratory PregabalinDosing: 25–50 mg tid; max dose 200 mg tid; period for evaluation unclear Potential AE: Dizziness, somnolence, xerostomia, edema, blurred vision, decreased concentration TramadolDosing: 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.

18 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 food Can 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 day May 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 day Folic 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

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. Bennett et al (2012) Support Care Cancer, 20:2959–2967 MildModerateSevere 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.

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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