Diagnostik und Therapie Chemotherapie-induzierter Polyneuropathien: Update 2016

Zusammenfassung

Die Chemotherapie-induzierte Neuropathie (CIPN) ist eine häufige Folgeerscheinung einer Tumortherapie mit Zytostatika wie Platinderivaten, Vincaalkaloiden, Taxanen, sogenannten „small molecules“ sowie modernen Antikörper-basierten Therapien. Als Folge der immer effektiver werdenden Chemotherapieformen und der höheren Langzeitüberlebensrate ist die Inzidenz der CIPN in den letzten Jahren stetig steigend. Die Ursachen und Mechanismen der CIPN auf zellulärer und molekularer Ebene sind dabei vielfältig. Beteiligt sind sowohl inflammatorische Mediatoren, Störungen der neuronalen Ionenkanalfunktion sowie Veränderungen der intrazellulären Signaltransmission. Weitere Mechanismen wie DNA-Schädigung, Einschränkung der DNA-Reparaturkapazität, mitochondriale Störungen, reaktive Sauerstoffspezies und ektope Aktivierung von Nozizeptoren begünstigen das Auftreten neuropathischer Schmerzsyndrome. Strukturelle Störungen der Spinalganglien und sensiblen Nerven führen zu vorwiegend sensorischen Störungen, wie Par-, Dys- und Hypästhesien mit der Folge einer deutlichen Einschränkung der Lebensqualität aber auch einem häufigen Abbruch einer notwendigen und effektiven Tumortherapie. Die Diagnosestellung erfolgt überwiegend klinisch, das Assessment zielt bei Patienten-orientierten Fragebögen auf die Erhebung der Störungen der verschiedenen Nervenfasertypen. Eine kausale Therapie ist bisher nicht möglich, häufig wird die Therapie beendet oder die Dosis der Chemotherapie reduziert. Nichtsdestotrotz sind symptomatische Therapiemöglichkeiten zur Therapie der assoziierten neuropathischen Schmerzen vorhanden. Diese Übersichtsarbeit soll die aktuellen Erkenntnisse der Mechanismen die zur CIPN führen beleuchten, die Diagnosestellung und Therapie der täglichen Praxis zeigen, sowie laufende Entwicklungen der kommenden Therapieformen der CIPN darstellen.

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition in patients undergoing treatment with commonly used agents such as platinum compounds, vinca alcaloids, taxanes, small molecules and antibody-based therapies. The incidence of CIPN is increasing as a consequence of better cancer treatments becoming available and increasing use of chemotherapy, and because it is a more frequently occurring side-effect with use of new chemotherapeutics. The mechanisms underlying this condition are diverse, and include an array of molecular and cellular contributions. Processes influenced by CIPN include increased expression of inflammatory mediators, changes in ion channels and neurotransmission, as well as changes in intracellular signaling and structures. Structural deficits in dorsal root ganglia and sensory nerves cause symptoms such as sensory loss, paresthesia, dysesthesia, numbness as well as neuropathic pain that result in patient suffering and also limit the therapeutic efficiency with a severe impairment of quality of life. DNA damage, alterations in cellular system repairs, mitochondrial changes, increased intracellular reactive oxygen species, glutamate signaling, MAP-kinases and nociceptor ectopic activation are among the events that trigger the onset of peripheral neurotoxicity and neuropathic pain. The diagnosis of CIPN is made principally on clinical grounds, and it is characterized by predominantly sensory symptoms. CIPN assessment relies mainly on patient-oriented questionnaires, but an international effort is ongoing to assess reliable and objective means to assess small and large fiber impairment. If CIPN occurs, the only effective strategies are dose reduction or discontinuation of chemotherapy. However, symptomatic treatment of mainly neuropathic pain symptoms is available and effective. The purpose of this review is to examine the basic mechanisms of neuropathy and currently available treatment options in the context of CIPN.

Schlüsselwörter

Chemotherapie - Neuropathischer Schmerz - Polyneuropathie

Keywords

chemotherapy - neuropathic pain - polyneuropathy

• Literatur

• 1 Kautio AL, Haanpaa M, Kautiainen H et al. Burden of chemotherapy-induced neuropathy – a cross-sectional study. Support Care Cancer 2011; 19: 1991-1996
• 2 Reyes-Gibby CC, Morrow PK, Buzdar A et al. Chemotherapy-induced peripheral neuropathy as a predictor of neuropathic pain in breast cancer patients previously treated with paclitaxel. J Pain 2009; 10: 1146-1150
• 3 Park SB, Lin CS, Krishnan AV et al. Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility. Oncologist 2011; 16: 708-716
• 4 McLeod HL. Precision medicine to improve the risk and benefit of cancer care: genetic factors in vincristine-related neuropathy. JAMA 2015; 313: 803-804
• 5 Diouf B, Crews KR, Lew G et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 2015; 313: 815-823
• 6 Geber C, Breimhorst M, Burbach B et al. Pain in chemotherapy-induced neuropathy – more than neuropathic?. Pain 2013; 154: 2877-2887
• 7 Treede RD, Jensen TS, Campbell JN et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-1635
• 8 Backonja MM, Attal N, Baron R et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain 2013; 154: 1807-1819
• 9 Kroigard T, Schroder HD, Qvortrup C et al. Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies. Eur J Neurology 2014; 21: 623-629
• 10 Sharma S, Venkitaraman R, Vas PR et al. Assessment of chemotherapy-induced peripheral neuropathy using the LDIFLARE technique: a novel technique to detect neural small fiber dysfunction. Brain Behav 2015; 5: e00354
• 11 Boehmerle W, Huehnchen P, Endres M et al. Neurologische Nebenwirkungen von Zytostatika. Akt Neuro 2014; 41: 21-34
• 12 Boehmerle W, Huehnchen P, Endres M. Chemotherapy-induced neuropathy. Nervenarzt 2015; 86: 156-160
• 13 Rosenberg B, Vancamp L, Krigas T. Inhibition of cell division in escherichia coli by electrolysis products from a platinum electrode. Nature 1965; 205: 698-699
• 14 van der Hoop RG, van der Burg ME, ten Bokkel Huinink WW et al. Incidence of neuropathy in 395 patients with ovarian cancer treated with or without cisplatin. Cancer 1990; 66: 1697-1702
• 15 Swenerton K, Jeffrey J, Stuart G et al. Cisplatin-cyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992; 10: 718-726
• 16 Kemp G, Rose P, Lurain J et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatin-induced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996; 14: 2101-2112
• 17 Roelofs RI, Hrushesky W, Rogin J et al. Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 1984; 34: 934-938
• 18 Thompson SW, Davis LE, Kornfeld M et al. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 1984; 54: 1269-1275
• 19 Strumberg D, Brugge S, Korn MW et al. Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 2002; 13: 229-236
• 20 Glendenning JL, Barbachano Y, Norman AR et al. Long-term neurologic and peripheral vascular toxicity after chemotherapy treatment of testicular cancer. Cancer 2010; 116: 2322-2331
• 21 Pfisterer J, Plante M, Vergote I et al. Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 2006; 24: 4699-4707
• 22 Anderson H, Wagstaff J, Crowther D et al. Comparative toxicity of cisplatin, carboplatin (CBDCA) and iproplatin (CHIP) in combination with cyclophosphamide in patients with advanced epithelial ovarian cancer. Eur J Cancer Clinical Oncol 1988; 24: 1471-1479
• 23 Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 2343-2351
• 24 de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 2938-2947
• 25 Land SR, Kopec JA, Cecchini RS et al. Neurotoxicity from oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: NSABP C-07. J Clin Oncol 2007; 25: 2205-2211
• 26 Wilson RH, Lehky T, Thomas RR et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002; 20: 1767-1774
• 27 Krishnan AV, Goldstein D, Friedlander M et al. Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle Nerve 2005; 32: 51-60
• 28 Doherty MK, Morris PG. Eribulin for the treatment of metastatic breast cancer: an update on its safety and efficacy. Int J Womens Health 2015; 7: 47-58
• 29 Vahdat LT, Garcia AA, Vogel C et al. Eribulin mesylate versus ixabepilone in patients with metastatic breast cancer: a randomized Phase II study comparing the incidence of peripheral neuropathy. Breast Cancer Res Treat 2013; 140: 341-351
• 30 Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979; 277: 665-667
• 31 Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst 2008; 13: 27-46
• 32 Mekhail TM, Markman M. Paclitaxel in cancer therapy. Expert Opin Pharmacother 2002; 3: 755-766
• 33 Loprinzi CL, Reeves BN, Dakhil SR et al. Natural history of paclitaxel-associated acute pain syndrome: prospective cohort study NCCTG N08C1. J Clin Oncol 2011; 29: 1472-1478
• 34 Garrison JA, McCune JS, Livingston RB et al. Myalgias and arthralgias associated with paclitaxel. Oncology (Williston Park) 2003; 17: 271-277 discussion 281-272, 286-278
• 35 Loprinzi CL, Maddocks-Christianson K, Wolf SL et al. The Paclitaxel acute pain syndrome: sensitization of nociceptors as the putative mechanism. Cancer J 2007; 13: 399-403
• 36 Reeves BN, Dakhil SR, Sloan JA et al. Further data supporting that paclitaxel-associated acute pain syndrome is associated with development of peripheral neuropathy: North Central Cancer Treatment Group trial N08C1. Cancer 2012; 118: 5171-5178
• 37 Winer EP, Berry DA, Woolf S et al. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J Clin Oncol 2004; 22: 2061-2068
• 38 Postma TJ, Vermorken JB, Liefting AJ et al. Paclitaxel-induced neuropathy. Ann Oncol 1995; 6: 489-494
• 39 Freilich RJ, Balmaceda C, Seidman AD et al. Motor neuropathy due to docetaxel and paclitaxel. Neurology 1996; 47: 115-118
• 40 Chaudhry V, Rowinsky EK, Sartorius SE et al. Peripheral neuropathy from taxol and cisplatin combination chemotherapy: clinical and electrophysiological studies. Ann Neurol 1994; 35: 304-311
• 41 Wasserheit C, Frazein A, Oratz R et al. Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity. J Clin Oncol 1996; 14: 1993-1999
• 42 Fazeny B, Zifko U, Meryn S et al. Vinorelbine-induced neurotoxicity in patients with advanced breast cancer pretreated with paclitaxel–a phase II study. Cancer Chemother Pharmacol 1996; 39: 150-156
• 43 Jones SE, Erban J, Overmoyer B et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncology 2005; 23: 5542-5551
• 44 Johnson IS, Armstrong JG, Gorman M et al. The Vinca Alkaloids: A New Class of Oncolytic Agents. Cancer Res 1963; 23: 1390-1427
• 45 Rowinsky E, Tolcher A. Chemotherapeutic Drugs: Microtubule-Targeting Drugs. In: Perry M. ed The Chemotherapy Source Book. Philadelphia: Lippincott Williams and Wilkins; 2001: 220-239
• 46 Powles TJ, Jones AL, Judson IR et al. A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer. Br J Cancer 1991; 64: 406-410
• 47 Holland JF, Scharlau C, Gailani S et al. Vincristine treatment of advanced cancer: a cooperative study of 392 cases. Cancer Res 1973; 33: 1258-1264
• 48 Graf WD, Chance PF, Lensch MW et al. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 1996; 77: 1356-1362
• 49 Bakshi N, Maselli RA, Gospe Jr SM et al. Fulminant demyelinating neuropathy mimicking cerebral death. Muscle Nerve 1997; 20: 1595-1597
• 50 Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 1969; 19: 367-374
• 51 Casey EB, Jellife AM, Le Quesne PM et al. Vincristine neuropathy. Clinical and electrophysiological observations. Brain 1973; 96: 69-86
• 52 Verstappen CC, Koeppen S, Heimans JJ et al. Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology 2005; 64: 1076-1077
• 53 Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: 2487-2498
• 54 Mohty M, Brissot E, Savani BN et al. Effects of bortezomib on the immune system: a focus on immune regulation. Biol Blood Marrow Transplant 2013; 19: 1416-1420
• 55 Richardson PG, Xie W, Mitsiades C et al. Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. J Clin Oncol 2009; 27: 3518-3525
• 56 Cata JP, Weng HR, Burton AW et al. Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 2007; 8: 296-306
• 57 Chen CI, Kouroukis CT, White D et al. Bortezomib is active in patients with untreated or relapsed Waldenstrom’s macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1570-1575
• 58 Gupta S, Pagliuca A, Devereux S et al. Life-threatening motor neurotoxicity in association with bortezomib. Haematologica 2006; 91: 1001
• 59 Richardson PG, Sonneveld P, Schuster MW et al. Reversibility of symptomatic peripheral neuropathy with bortezomib in the phase III APEX trial in relapsed multiple myeloma: impact of a dose-modification guideline. Br J Haematol 2009; 144: 895-903
• 60 Moreau P, Pylypenko H, Grosicki S et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011; 12: 431-440
• 61 Younes A, Gopal AK, Smith SE et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 2012; 30: 2183-2189
• 62 Zinzani PL, Viviani S, Anastasia A et al. Brentuximab vedotin in relapsed/refractory Hodgkin’s lymphoma: the Italian experience and results of its use in daily clinical practice outside clinical trials. Haematologica 2013; 98: 1232-1236
• 63 Pastorelli F, Derenzini E, Plasmati R et al. Severe peripheral motor neuropathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma 2013; 54: 2318-2321
• 64 Ogura M, Tobinai K, Hatake K et al. Phase I/II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin’s lymphoma or systemic anaplastic large-cell lymphoma. Cancer Sci 2014; 105: 840-846
• 65 Pro B, Advani R, Brice P et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012; 30: 2190-2196
• 66 Castelli R, Gritti G, Cannavo A et al. Successful management with intravenous immunoglobulins in alemtuzumab-induced acute inflammatory demyelinating neuropathy: clinical report of three patients. Immunopharmacol Immunotoxicol 2012; 34: 717-720
• 67 Hodi FS, O’Day SJ, McDermott DF et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363: 711-723
• 68 Thaipisuttikul I, Chapman P, Avila EK. Peripheral neuropathy associated with ipilimumab: a report of 2 cases. J Immunother 2015; 38: 77-79
• 69 Attal N, Cruccu G, Baron R et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010; 17: e1113-e1188
• 70 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, placebo-controlled, crossover trial (N00C3). Cancer 2007; 110: 2110-2118
• 71 Tsavaris N, Kopterides P, Kosmas C et al. Gabapentin monotherapy for the treatment of chemotherapy-induced neuropathic pain: a pilot study. Pain Med 2008; 9: 1209-1216
• 72 Smith EM, Pang H, Cirrincione C et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 2013; 309: 1359-1367
• 73 Zimmerman C, Atherton PJ, Pachman D et al. MC11C4: a pilot randomized, placebo-controlled, double-blind study of venlafaxine to prevent oxaliplatin-induced neuropathy. Support Care Cancer 2015;
• 74 Streckmann F, Kneis S, Leifert JA et al. Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy. Ann Oncol 2014; 25: 493-499
• 75 Ewertz M, Qvortrup C, Eckhoff L. Chemotherapy-induced peripheral neuropathy in patients treated with taxanes and platinum derivatives. Acta Oncol 2015; 54: 587-591
• 76 Apfel SC, Arezzo JC, Lipson L et al. Nerve growth factor prevents experimental cisplatin neuropathy. Ann Neurol 1992; 31: 76-80
• 77 Aloe L, Manni L, Properzi F et al. Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis. Auton Neurosci 2000; 86: 84-93
• 78 Chattopadhyay M, Goss J, Wolfe D et al. Protective effect of herpes simplex virus-mediated neurotrophin gene transfer in cisplatin neuropathy. Brain 2004; 127: 929-939
• 79 Friesland A, Weng Z, Duenas M et al. Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR. Neurotoxicology 2014; 45: 81-90
• 80 Cervellini I, Bello E, Frapolli R et al. The neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction of antitumor activity in 13762 adenocarcinoma-bearing rats. Neurotox Res 2010; 18: 151-160
• 81 Yoon MS, Katsarava Z, Obermann M et al. Erythropoietin overrides the triggering effect of DNA platination products in a mouse model of cisplatin-induced neuropathy. BMC Neurosci 2009; 10: 77
• 82 Bianchi R, Gilardini A, Rodriguez-Menendez V et al. Cisplatin-induced peripheral neuropathy: neuroprotection by erythropoietin without affecting tumour growth. Eur J Cancer 2007; 43: 710-717
• 83 Pisano C, Pratesi G, Laccabue D et al. Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine. Clinical Cancer Res 2003; 9: 5756-5767
• 84 Tredici G, Cavaletti G, Petruccioli MG et al. Low-dose glutathione administration in the prevention of cisplatin-induced peripheral neuropathy in rats. Neurotoxicology 1994; 15: 701-704
• 85 Zhu J, Chen W, Mi R et al. Ethoxyquin prevents chemotherapy-induced neurotoxicity via Hsp90 modulation. Ann Neurol 2013; 74: 893-904
• 86 Leal AD, Qin R, Atherton PJ et al. North Central Cancer Treatment Group/Alliance trial N08CA-the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled study. Cancer 2014; 120: 1890-1897
• 87 Babu A, Prasanth KG, Balaji B. Effect of curcumin in mice model of vincristine-induced neuropathy. Pharm Biol 2015; 53: 838-848
• 88 Al Moundhri MS, Al-Salam S, Al Mahrouqee A et al. The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: some behavioral, biochemical, and histopathological studies. J Med Toxicol 2013; 9: 25-33
• 89 Park HJ, Lee HG, Kim YS et al. Ginkgo biloba extract attenuates hyperalgesia in a rat model of vincristine-induced peripheral neuropathy. Anesthesia Analgesia 2012; 115: 1228-1233
• 90 Ozturk G, Anlar O, Erdogan E et al. The effect of Ginkgo extract EGb761 in cisplatin-induced peripheral neuropathy in mice. Toxicol Appl Pharmacol 2004; 196: 169-175