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Chemotherapy-Induced Neuropathy: Prevention and Treatment

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Chemotherapy-Induced Neuropathy: Prevention and Treatment View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Helsingin yliopiston digitaalinen arkisto Department of Oncology Helsinki University Central Hospital University of Helsinki Finland Chemotherapy-induced neuropathy: prevention and treatment Anna-Liisa Kautio ACADEMIC DISSERTATION To be presented, with the permission of the Medical Faculty of the University of Helsinki, for public discussion in Lecture Hall 3, Biomedicum Helsinki 1, Haartmanninkatu 8, Helsinki on 18 May 2012, at 12 noon. Helsinki Supervisors Professor Tiina Saarto Docent Maija Haanpää, Department of Oncology Department of Neurosurgery University of Helsinki University of Helsinki Helsinki; Helsinki, Finland University of Tampere Tampere, Finland Reviewers Professor Johanna Mäenpää Professor Seppo Soinila University of Tampere University of Turku Tampere, Finland Turku, Finland Official opponent Professor Vesa Kataja University of Eastern Finland Kuopio, Finland ISBN 978-952-10-7944-3 (paperback) ISBN 978-952-10-7945-0 (pdf) Unigrafia Oy Helsinki 2012 2 Lila, Jarno and Salla 3 List of original publications ............................................................................ 6 Abbreviations................................................................................................. 7 Abstract ......................................................................................................... 8 Introduction.................................................................................................. 10 Review of the literature................................................................................ 12 Anatomy of peripheral nervous system...................................................................... 12 Disorders of the peripheral nervous system............................................................... 14 Neuropathic pain........................................................................................................ 15 Peripheral neuropathies related to malignancies ....................................................... 16 Chemotherapy induced peripheral neuropathy .......................................................... 18 Neurotoxic agents...................................................................................................... 27 Prevention of CIPN .................................................................................................... 41 Treatment of CIPN..................................................................................................... 49 Aims of the present study............................................................................ 53 Patients and methods.................................................................................. 54 Patients...................................................................................................................... 54 Methods ..................................................................................................................... 58 Statistical methods ...................................................................................... 62 Statistical analyses .................................................................................................... 62 Ethical considerations................................................................................................ 64 Results......................................................................................................... 65 Burden of CIPN (study I)............................................................................................ 65 Amitriptyline in prevention and treatment of CIPN (studies II, III)............................... 66 Assesment (study IV)................................................................................................. 69 Intraepidermal nerve fiber density (study V)............................................................... 69 4 Discussion ................................................................................................... 70 Prevalence and burden of chemotherapy-induced neuropathy.................................. 70 Assessment of chemotherapy-induced neuropathy ................................................... 71 Grading of CIPN......................................................................................................... 72 Intraepithelial nerve fibers.......................................................................................... 73 Prevention of CIPN .................................................................................................... 74 Treatment of CIPN..................................................................................................... 75 Challenges in prevention and treatment of CIPN ....................................................... 75 Summary and Conclusions ......................................................................... 77 Acknowledgements ..................................................................................... 79 References .................................................................................................. 81 Original Publications.................................................................................... 94 5 LIST OF ORIGINAL PUBLICATIONS This thesis is based on the following original publications: (I) Kautio AL, Haanpää M, Kautiainen H, Kalso E, Saarto T. Burden of chemotherapy- induced neuropathy- a cross-sectional study. Support Care Cancer. 2011;19:1991-6. (II) Kautio AL, Haanpää M, Saarto T, Kalso E. Amitriptyline in the treatment of chemotherapy-induced neuropathic symptoms. J Pain Symptom Manage. 2008;35:31-9. (III) Kautio AL, Haanpää M, Leminen A, Kalso E, Kautiainen H, Saarto T. Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms. Anticancer Res. 2009;29:2601- 6. (IV) Kautio AL, Haanpää M, Kautiainen H, Leminen A, Kalso E, Saarto T. Oxaliplatin Scale and National Cancer Institute-Common Toxicity Criteria in the Assessment of Chemotherapy-induced Peripheral Neuropathy. Anticancer Res. 2011;31:3493-6. (V) Koskinen M, Kautio AL, Haanpää M, Haapasalo H, Kellokumpu-Lehtinen P, Saarto T, Hietaharju A. Intraepidermal nerve fiber density in cancer patients receiving ajduvant chemotherapy. Anticancer Res. 2011;31:4413-6. 6 ABBREVIATIONS ADL = activities of daily living CIPN = chemotherapy induced peripheral neuropathy DNA = deoxyribonucleic acid DRG = dorsal root ganglion ECOG = Eastern Cooperative Oncology Group EMA = European Medicines Agency EORTC QLQ-C30 = European Organization for Research and Treatment of Cancer item 30 of the quality of life questionnaire FDA = the United States Food and Drug Administration Ca = calcium Mg = magnesium HIV = human immunodeficiency virus IENF = intraepidermal nerve fiber NCI-CTC = the National Cancer Institute – Common Toxicity Criteria NRS = Numerical rating scale PGP 9.5 = protein-gene-product 9.5 PHN = postherpetic neuralgia q3w = every three week treatment schedule QoL = quality of life QST = quantitative sensory testing SNRI = serotonin-noradrenalin reuptake inhibitor TCAs = tricyclic antidepressants TNF- = tumor necrosis factor alfa TNS = Total Neuropathy Score TRPA1 = Transient Receptor Potential Ankyrin 1 TRPM8 = Transient Receptor Potential Melastatin 8 TRPV1 = Transient Receptor Potential Vanilloid 1 VAS = Visual Analogue Scale VRS = Verbal rating scale 7 ABSTRACT Aims The present study aimed to investigate the effect of amitriptyline in prevention (study III) and treatment (study II) of chemotherapy-induced peripheral neuropathy (CIPN). The secondary aims were to evaluate the prevalence and discomfort of CIPN in a clinical cohort predisposed to neurotoxic chemotherapy agents (study I), grading of neurotoxicity (study IV) and the changes in intraepidermal nerve fiber (IENF) density during the neurotoxicity treatment (study V). Patients The study included three cancer patient populations treated with neurotoxic chemotherapy at Helsinki University Hospital, Department of Oncology (studies I-IV) or Gynecology (study III) and Tampere University Hospital, Department of Oncology (study V). The first study population was screened between January 2002 and June 2004 from 448 patients aged 20 to 70 years, of whom 152 had neuropathic symptoms and were hence eligible for evaluation of the burden of neuropathic symptoms (I). Of those 152 symptomatic patients 33 patients had sensory neuropathic symptoms (numbness, tingling or pain) of at least moderate severity and were randomised to treatment study (II). Between February 2003 and May 2006 104 patients without previous neuropathy who started neurotoxic chemotherapy were randomized to the prevention study (III). Two different neurotoxicity scales were used with this population (IV). The fifth study consisted of 12 patients aged from 18 to 70 years starting adjuvant chemotherapy with taxanes or platinum derivatives (V). Methods In the first study (I) a questionnaire of chemotherapy adverse effects and neuropathy symptoms was used for screening. The intensity of the neuropathic symptoms was assessed with a Visual Analogue Scale (VAS) (I-III, V). During the clinical visits the patients were evaluated with physical examination including neurological status (I-III, V). Neuropathy 8 was scored according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) and Oxaliplatin Scales (II-V), and quality of life (QoL) with the European Organization for Research and Treatment of Cancer item 30 of the
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