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1 REVIEW ARTICLE Yonsei University Wonju College of Medicine Wonju, Korea Ik Yong Kim, M.D. 11

2 Table 1. Cancer-related causes Neuropathy Cause Neurotoxicity related cancer treatment Tumor pathology Nutritional deficiencies Metabolic disturbances Opportunistic infections Paraneoplastic neurologic disorders (PND), or nervous dysfunction caused by the remote effects such as surgery, radiotherapy, and chemotherapy direct compression or infiltration of nerves by primary or metastatic lesions Table 2. The abnormal sensation of neuropathic pain Spontaneous pain Hyperesthesia (increased feeling) Paresthesia (Beyond feeling) Dysesthesia (impaired feeling) Hyperalgesia (increased pain) Hyperpathia (increased suffering') Allodynia (other pain) Hypoesthesia (decreased feeling') Hypoalgesia (decreased pain') Analgesia ('no pain') 1.Sensory nerves affect sensation 2.Motor nerves affect muscles and motion 3.Autonomic nerves affect internal organs Burning, shooting, lancinating increased sensitivity to stimulation, excluding the special senses abnormal nonpainful sensation that may be spontaneous or evoked (tingling) abnormal pain that may be spontaneous or evoked (unpleasant tingling) an exaggerated painful response to abnormally noxious stimulus an exaggerated painful response evoked by noxious or non-noxious stimulus a painful response to a normally non-noxious stimulus(for example, light touch is perceived as burning pain) involves a change in quality of sensation, whether touch or heat or cold decreased sensitivity to stimulation, excluding the special senses diminished pain in response to a normally painful stimulus complete loss of pain sensation, namely absence of pain in response to stimulation which would normally be painful Painful paresthesia, dysesthesia, cold-sensitivity, tingling, numbness, alteration in vibration and proprioception, or a change in reflexes Muscle weakness Orthostatic hypotension, constipation, urinary retention, irregular heart rate, and sexual dysfunction. 12 Ik Yong Kim

3 Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1: Table 3. Common Chemotherapeutic drugs Known to Induce Neuropathy Drug Incidence Onset Dose Clinical Manifestation Recovery Platinum compounds 28%-100% (overall) 300 mg/m 2 Symmetrical painful paresthesia or Partial, symptoms may Cisplatin + paclitaxel: 7%-8% numbness in a stocking-glove distribution, progress for months after (severe*) sensory ataxia with gait dysfunction discontinuation Carboplatin 6%-42% (overall) mg/m 2 Similar to cisplatin but milder Similar to cisplatin + paclitaxel: 4%-9% (severe) Oxaliplatin (acute) 85%-95% (overall) any Cold-induced painful dysesthesia Resolution within a week Oxaliplatin (persistent/ FOLFOX: 10%-18% mg/m 2 Similar to cisplatin Resolution in 3 months, may chronic) (severe) persist long-term Vinca alkaloids 30%-47% (overall) 4-10 mg Symmetrical tingling paresthesia, loss of Resolution usually within Vincristine, vinblastine, ankle stretch reflexes, constipation, 3 months, may persist for vinorelbine, vindesine occasionally weakness, and gait dysfunction vincristine Taxanes 57%-83% (overall), mg/m 2 Symmetrical painful paresthesia or Resolution usually within 3 months, Paclitaxel 2%-33% (severe) numbness in stocking-glove distribution, may persistmay persist + Cisplatin: 7%-8% decreased vibration or proprioception, (severe) occasionally weakness, sensory ataxia, + Carboplatin: 4%-16% and gait dysfunction (severe) Abraxane (albumin-bound 73% (overall) unclear Similar to paclitaxel Resolution usually within 3weeks paclitaxel) 10%-15% (severe) Docetaxel 11%-64% (overall) mg/m 2 Similar to paclitaxel Resolution usually within 3 months, 3%-14% (severe) may persist Others Bortezomib 31%-55% (overall) 1.3 mg/m 2 Painful paresthesia, burning sensation, Resolution usually within 3 months, 9%-22% (severe) occasionally weakness, sensory ataxia, may persist and gait dysfunction. Rare autonomic dysfunction including orthostatic hypotension Ixabepilone 63% (overall), 14% mg/m 2 Painful paresthesia, burning sensation Resolution in 4-6 weeks (severe) + capecitabine: 67% (overall), 21% (severe) Thalidomide 25%-83% (overall), 20 g Symmetrical tingling or numbness, pain. May persist for over 1 year 15%-28% (severe) Occasionally weakness, sensory ataxia, and gait dysfunction Lenalidomide 10%-23% (overall), unclear Similar to thalidomide Unclear (thalidomide analog) 1%-3% (severe) 13

4 Fig. 1. Symptoms of chemotherapy-induced peripheral neuropathy Ik Yong Kim

5 Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1: Table 4. Key Points to Report During Clinical Assessment of CIPN Personal history of neuropathy and CIPN from previous cancer treatment Personal and family history of hereditary neuropathy (patients with Charcot-Marie Tooth disease should avoid vincristine-based chemotherapy) Related comorbid conditions (e.g., diabetes, HIV, Guillain-Barre syndrome, CIDP, radiculopathy) Alcohol use Temporal profile: regimen dosage, duration, schedule, coasting ± effects Symptoms Type: sensory, motor, or autonomic Distribution: distal symmetric or asymmetric Severity Pain assessment: BPI, LANSS, NPS Time course of CIPN, including onset and resolution of symptoms Treatment delays or discontinuation related to CIPN Physical Examination Sensory assessment: light touch, vibration, proprioception, pin-prick, temperature Deep tendon reflex: presence, absence, diminishment Motor weakness Autonomic symptoms (e.g., constipation, orthostatic hypotension, urinary dysfunction, sexual dysfunction) Related musculoskeletal abnormalities (e.g., hammertoes, high or flattened arches) Sample Questions for Patient Do you feel numbness or tingling in your hands or feet? Do you feel pain in your hands and feet? (Rate it on a scale of 0 to 10.) Do you feel like having gloves and stockings on? Do these sensations bother you? Are they getting worse? Do you feel weakness in your arms and legs? Do you drop things often? Have you fallen recently? Do you have difficulty walking or climbing stairs? Do these sensations interfere with your work or daily activities? Examples of Functional Assessment Skill Tests Getting up and straight-line walking (observe gait and balance) Name writing Buttoning Timed pellet retrieval (for clinical trials) Pegboard test (for clinical trials) 15

6 Table 5. Commonly Used Physician-Based Grading Scales for Evaluation of CIPN Scale Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 WHO 9 Paresthesias and/ Severe paresthesias Intolerable Paralysis NA or decreased and/or mild weakness paresthesias and/or tendon reflexes marked motor loss ECOG 10 Decreased deep Absent deep tendon Disabling sensory Respiratory dysfunction NA tendon reflexes, reflexes, severe loss, severe peripheral secondary to weakness, mild paresthesias paresthesias or neuropathic pain, obstipation requiring or constipation constipation, obstipation, severe surgery, mild weakness weakness, bladder dysfunction paralysis confining patient to bed/wheelchair NCI-CTCAE (v3.0) 11 Asymptomatic: Sensory alteration or Sensory alteration Disabling Death Neuropathy-sensory loss of deep tendon Paresthesia (including or paresthesia reflexes or paresthesia tingling), interfering with interfering with ADL (including tingling) function but but not interfering with not with ADL function Neuropathy-motor Asymptomatic, Symptomatic Weakness interfering with ADL: Lifet hreatening: Death weakness by Weakness interfering bracing or assistance to walk Disabling (e.g., paralysis) exam/testing only with function but indicated not interfering with ADL Ajani 8 Paresthesia, Mild objective Severe paresthesia, Complete NA Sensory decreased deep abnormality, absence of moderate objective sensory loss, loss tendon reflexes deep tendon reflexes, abnormality, of function mild to moderate severe functional functional abnormality abnormality Motor Mild or transient Persistent moderate Unable to ambulate Complete paralysis NA muscle weakness weakness but ambulatory 16 Ik Yong Kim

7 Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1: Table 6. Current proposed Agents for Preventing CIPN Drug Mechanism of Action Findings From Randomized Controlled Trials (Number of cases ) Agents with Positive Findings in Randomized Controlled Trials Vitamin E Antioxidant/minimizes neuronal damage CIPN incidence and severity reduced (30-47) CIPN severity reduced (81) Ongoing trial: NCT * Ca++/Mg++ Facilitates Na channel function; binds oxalate CIPN incidence reduced (104) (metabolite of oxaliplatin) Glutamine Upregulation of nerve growth factor CIPN incidence reduced (86) Glutathione Hampers accumulation of platinum adducts CIPN incidence reduced/trend towards reduction in DRG (50-151) N-acetylcysteine Antioxidant; increases blood concentrations of glutathione Incidence of grade 2-4 neuropathy reduced (14) Oxcarbazepine Inhibits high-frequency firing of nerves; Neuropathy incidence reduced (32) modulates ion channels Xaliproden Non-peptide neurotrophic agent Shift of CIPN from grade 3 to grade 2 (649) Ongoing trial: NCT * Agents With Negative Findings in Randomized Controlled Trials Amifostine Detoxifies chemotherapy; facilitates DNA Not effective (66) repair Improvement on NCI-CTC scale but not on patient questionnaire (72) Nimodipine Calcium channel antagonist Not effective; randomized trial closed early (51) Org 2766 Nerve growth factor family, Vibration perception maintained (55) adrenocorticotrophic hormone analog Not effective ( ) rhulif Neuroprotective cytokine Not effective (117) Additional Agents Being Tested in Ongoing Phase III Randomized Controlled Trials Vitamin B12/B6 Essential for nerve function Ongoing trial: NCT Acetyl-L-carnitine Oxidation of free fatty acids/nerve regeneration New trial: NCT * Alpha lipoic acid Antioxidant Ongoing trial: NCT * 17

8 18 Ik Yong Kim

9 Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1: Table 7. Common Agents for Pain Management in Peripheral Neuropathy Drug Starting Dose Titration Maximum Dose Duration of Adequate Trial Potential Side Effects Duloxetine mg/d No evidence that 120 mg/d 2 wk Nausea, xerostomia, constipation, higher dose is more effective diarrhea Gabapentin* mg increase by 3600 mg 1-2 wk at max Somnolence, dizziness, GI nightly or mg 3 (depending on tolerated dose symptoms, mild edema, mg 3 times/day, every absorption) cognitive impairment (elderly), times/d 1-7 days exacerbation of gait problems 5% Lidocaine Maximum of 3 Non-applicable 3 patches 2 wk Rash/erythema patch patches daily Opioids 5-15 mg every Convert to longacting No ceiling effect 4-6 wk Constipation, nausea, (oxycodone, 4 h after 1 wk, vomiting (self-limited), morphine, titrate based on sedation, confusion, methadone) breakthrough use respiratory depression Pregabalin mg 3 Increase by 50 mg/dose after 200 mg 3 times/d Unclear (likely Dizziness, somnolence, times/d 1 wk 2-4 wk) xerostomia, edema, blurred vision, decreased concentration Tramadol 50 mg 1-2/d Increase by mg/d (100 4 wk Dizziness, constipation, mg/d, individual mg 4 times/d); nausea, somnolence, doses every 3-7 days elderly 300 mg/d orthostatic hypotension, increased risk of seizure, serotonin syndrome Tricyclic Starting dose: Increase by mg; may 6-8 wk; 1-2 wk Cardiovascular disease antidepressants mg mg every 3-7 days increase if blood at max dose (needs screening), anticholinergic (amitriptyline,* nightly level of drug effects, interact with drugs metabolized nortriptyline,* plus metabolite by cytochrome P450 desipramine) <100 ng/ml 2D6 (e.g., cimetidine, phenothiazine) 19

10 REFERENCES 1. Hausheer FH, Schilsky RL, Bain S, et al. Diagnosis, management, and evaluation of chemotherapy-induced peripheral neuropathy. Semin Oncol 2006; 33: Stubblefield MD, Burstein HJ, Burton AW, Custodio, CM, Deng GE, Ho M et a.l NCCN Task Force Report:Management of Neuropathy in Cancer. J NCCN 2009; 7: S5; Park SB, Krishnan AV, Lin CS, et al. Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Curr Med Chem 2008;15: Park SB, Goldstein D, Lin CS, et al. Acute abnormalities of sensory nerve function associated with oxaliplatin-induced neurotoxicity. J Clin Oncol 2009;27: Simpson DA, Tagliati M, Gonzales-Duarte A, Mongello S. Neurologic manifestations. In: Mildvan D, ed. International Atlas of AIDS, 4th edition. Hoboken, NJ: Current Medicine Group LLC; 2007; 6. Becouarn Y, Ychou M, Ducreux M, et al. Phase II trial of oxaliplatin as first-line chemotherapy in metastatic colorectal cancer patients. Digestive Group of French Federation of Cancer Centers. J Clin Oncol 1998; 16: Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst 2008;13: Park SB, Lin CS, Krishnan AV, et al: Oxaliplatin-induced neurotoxicity: Changes in axonal excitability precede development of neuropathy. Brain 2009;132: Nikcevich DA, Grothey A, Sloan JA, et al. Effect of intravenous calcium and magnesium (IV CaMg) on oxaliplatin-induced sensory neurotoxicity (snt) in adjuvant colon cancer: results of the phase III placebo-controlled, double-blind NCCTG trial N04C7 [abstract]. J Clin Oncol 2008;26(Suppl 18S):Abstract Haller DG. Safety of oxaliplatin in the treatment of colorectal cancer. Oncology (Williston Park) 2000;14(12 Suppl 11): de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000;18: Ajani JA, Welch SR, Raber MN, et al. Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 1990;8: Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981;47: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5: National Cancer Institute. National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0. Available at: electronic_applications/ docs/ctcaev3.pdf. Accessed July 8, Cavaletti G, Frigeni B, Lanzani F, et al. The Total Neuropathy Score as an assessment tool for grading the course of chemotherapy induced peripheral neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale. J Peripher Nerv Syst 2007;12: Grothey A, Nikcevich DA, Sloan JA, et al: Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol 2011;29: Hochster HS, Grothey A, Childs BH: Use of calcium and 20 Ik Yong Kim

11 Korean Journal of Clinical Oncology Summer 2011;Vol.7,NO.1: magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 25:4028-9, Vajda FJ: Neuroprotection and neurodegenerative disease. J Clin Neurosci 2002;9: Gamelin L, Boisdron-Celle M, Delba R, et al: Prevention of oxaliplatinrelated neurotoxicity by calcium and magnesium infusions: A retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res 2004;10: Knijn N, Tol J, Koopman M, et al: The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients. Eur J Cancer 2011;47: Lersch C, Schmelz R, Eckel F, Erdmann J, Mayr M, Schulte- Frohlinde E, et al. Prevention of oxaliplatin-induced peripheral sensory neuropathy by carbamazepine in patients with advanced colorectal cancer. Clin Colorectal Cancer 2002;2: Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, et al. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2002;20: Tournigand C, Cervantes A, Figer A, Lledo G, Flesch M, Buyse M, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer--a GERCOR study. J Clin Oncol 2006;24: Mattioli R, Massacesi C, Recchia F, Marcucci F, Cappelletti C, Imperatori L, et al. High activity and reduced neurotoxicity of bifractionated oxaliplatin plus 5-fluorouracil/leucovorin for elderly patients with advanced colorectal cancer. Ann Oncol 2005;16: Hammack JE, Michalak JC, Loprinzi CL, et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cisplatinum- induced peripheral neuropathy. Pain 2002;98: Kautio AL, Haanpaa M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage 2008;35: Rao RD, Flynn PJ, Sloan JA, et al. Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3. Cancer 2008;112: Rao RD, Michalak JC, Sloan JA, et al. Efficacy of gabapentin in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebocontrolled, crossover trial (N00C3). Cancer 2007;110: Barton D, Wos E, Qin R, et al. A randomized controlled trial evaluating a topical treatment for chemotherapy-induced neuropathy: NCCTG trial N06CA [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract Durand JP, Deplanque G, Gorent J, et al. Efficacy of venlafaxine for the prevention and relief of acute neurotoxicity of oxaliplatin: results of EFFOX, a randomized, double-blinded, placebo-controlled prospective study [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA 1998;280: Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med 2005;352: Wernicke JF, Pritchett YL, D Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006;67: Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150: Cruccu G, Aziz TZ, Garcia-Larrea L, et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007;14: Daousi C, Benbow SJ, MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005;22: Nicholas PK, Kemppainen JK, Canaval GE, et al. Symptom management and self-care for peripheral neuropathy in HIV/ AIDS. AIDS Care 2007;19: Haythornthwaite JA, Benrud-Larson LM. Psychological assessment and treatment of patients with neuropathic pain. Curr Pain Headache Rep 2001;5:

Neuropathy in cancer patients or patients with peripheral neuropathy is a common and often difficult and debilitating complication of cancer or the treatment-related.

12 Management of peripheral neuropathy for cancer patients Department of Surgery, Yonsei University Wonju College of Medicine Wonju, Korea Ik Yong Kim, M.D. Neuropathy in cancer patients or patients with peripheral neuropathy is a common and often difficult and debilitating complication of cancer or the treatment-related. Chemotherapy-Induced Peripheral Neuropathy (CIPN) is most widely reported and has been the focus of research efforts among the various types of neuropathies in cancer patients. Platinum-based drugs, such as cisplatin and oxaliplatin, are well-known for inducing chronic sensory neuropathies, but their acute and motor neurotoxicities are less well characterized. Multidisciplinary team was charged with the review the literature and discussion intervention strategies currently available to patients as well as areas that require research efforts for the possible prevention, diagnosis, and management of peripheral neuropathy. Effective management of neuropathy or CIPN depends on early diagnosis and an understanding of its underlying causes in the individual patient. Patients with neuropathic pain (NP) are also challenging to manage and evidencebased clinical recommendations for pharmacologic management are needed. The objectives of this article are to discuss: Systematic literature reviews, randomized clinical trials, and existing guidelines were evaluated in prevention, assessment and treatment of the various types of neuropathies in cancer patients 22 Ik Yong Kim

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R