Neurologische Nebenwirkungen von Zytostatika

Zusammenfassung

Die Zahl der jährlich mit einer zytostatischen Chemotherapie behandelten Patienten nimmt vor dem Hintergrund einer steigenden Inzidenz und Prävalenz von Tumorerkrankungen kontinuierlich zu. Bedingt durch bessere supportive Therapien insbesondere hämatologischer Nebenwirkungen und einer gesteigerten Lebenserwartung der Patienten rücken neurologische Therapiefolgen zunehmend in den Vordergrund. Es ist bemerkenswert, dass neurotoxische Phänomene, nach hämatologischen- bzw. gastroenterologischen Toxizitäten, trotz des postmitotischen Zustands von Nervenzellen zu den häufigsten Nebenwirkungen vieler Zytostatika zählen. Diese pathogenetisch schlecht verstandenen unerwünschten Arzneimittelwirkungen (UAW) stellen ein erhebliches medizinisches Problem dar, da sie einerseits häufig eine Dosislimitierung und damit letztlich eine suboptimale Tumortherapie bedingen und andererseits zu einer erheblichen, oft langanhaltenden Einschränkung der Lebensqualität für die Betroffenen führen. Trotz des exakt definierten und vorab bekannten Schädigungszeitpunkts gibt es kaum validierte therapeutische bzw. präventive Ansätze für neurotoxische Nebenwirkungen von Zytostatika. Die Kenntnis Chemotherapie-induzierter neurologischer Pathologien im peripheren und zentralen Nervensystem ist, angesichts der Vielzahl möglicher Symptome, zur differenzialdiagnostischen Abgrenzung von anderen Erkrankungsentitäten von hoher praktischer Relevanz. Um zunehmend komplexeren Behandlungsprotokollen und einer steigenden Zahl zytostatischer Medikamente Rechnung zu tragen, werden im Rahmen dieser Übersichtsarbeit relevante neurologische Nebenwirkungen gängiger Zytostatika im peripheren und zentralen Nervensystem dargestellt und, sofern verfügbar, mögliche therapeutische Strategien aufgezeigt. Konkret widmet sich der erste Teil dieser Übersicht Nebenwirkungen im peripheren Nervensystem welche durch Substanzen aus der Gruppe der Platinverbindungen (Cisplatin, Carboplatin, Oxaliplatin), Vincaalkaloide (Vincristin), Taxane (Paclitaxel, Docetaxel), Proteasominhibitoren (Bortezomib) und Antikörperkonjugate (Brentuximab-Vedotin) hervorgerufen werden. Der zweiten Teil dieser Arbeit fokussiert sich auf neurotoxische UAW im zentralen Nervensystem, hervorgerufen durch Medikamente aus der Gruppe der Antimetabolite (Methotrexat, 5-Fluoruracil, Cytarabin, Fludarabin), Alkylanzien (Ifosfamid), Platin-Verbindungen (Cis-Platin), Vincaalkaloide (Vincristin), Rezeptor-Tyrosinkinase Inhibitoren (Imatinib, Sorafenib, Sunitinib) und Biologicals (Bevacizumab). Zuletzt wird im dritten Teil auf das ätiologisch noch umstrittene Krankheitsbild der Chemotherapie-induzierten kognitiven Defizite eingegangen.

Abstract

With an increasing incidence of malignancies, the number of patients treated with cytostatic chemotherapy is rising continuously. Neurological sequelae of tumor therapy are a growing concern as improved therapy protocols increase the life expectancy of patients. Despite the postmitotic state of neurons, neurotoxic phenomena are amongst the most common side effects of many cytostatic drugs, second only to hematological or gastroenterological toxicities. Chemotherapy-induced neurotoxic phenomena represent a medical problem as they can be dose limiting, thus preventing optimal therapy, and lead to long-lasting limitations in quality of life. There are hardly any validated therapeutic or preventive approaches to neurotoxic side effects of cytostatic drugs. In view of the large number of possible neurotoxic symptoms, knowledge of chemotherapy-induced neurological pathologies in the central and peripheral nervous system is of practical relevance for making a differential diagnosis.

In the context of ever more complex treatment protocols and increasing number of cytostatic drugs, we review the neurological side effects of chemotherapeutic drugs in general use in the peripheral and central nervous system and discuss potential therapeutic strategies. In the first part, this review focuses on side effects in the peripheral nervous system of platinum-based antineoplastic drugs (cisplatin, carboplatin, oxaliplatin), vincaalcaloids (vincristine), taxanes (paclitaxel, docetaxel), proteasome inhibitors (bortezomib) and biologicals (brentuximab-vedotin). The second part is dedicated to neurotoxic side effects in the central nervous system induced by antimetabolites (methotrexate, 5-fluoruracil, cytarabine, fludarabine), alkylating agents (ifosfamide), platinum-based antineoplastic drugs (cisplatin), vincaalcaloids (vincristine), receptor tyrosine kinase inhibitors (imatinib, sorafenib, sunitinib) and biologicals (bevacizumab). In the third part of this review we summarize current data on the illness entity of chemotherapy-induced cognitive impairment, whose etiology continues to be controversial.

Schlüsselwörter

Chemotherapie induzierte Neuropathie - neuropathischer Schmerz - Neurotoxizität - Post chemotherapy ­cognitive impairment - posteriores reversibles Enzephalopathie-Syndrom

Keywords

chemotherapy induced neuropathy - neuropathic pain - neurotoxicity - post chemotherapy ­cognitive impairment - posterior reversible ­encephalopathy syndrome

• Literatur

• 1 Binda D, Vanhoutte EK, Cavaletti G et al. Rasch-built overall disability scale for patients with chemotherapy-induced peripheral neuropathy (CIPN-R-ODS). Eur J Cancer 2013; 49: 2910-2918
• 2 Cavaletti G, Cornblath DR, Merkies IS et al. The chemotherapy-induced peripheral neuropathy outcome measures standardization study: from consensus to the first validity and reliability findings. Ann ­Oncol 2013; 24: 454-462
• 3 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
• 4 Grunberg SM, Sonka S, Stevenson LL et al. Progressive paresthesias after cessation of therapy with very high-dose cisplatin. Cancer Chemother Pharmacol 1989; 25: 62-64
• 5 Grochow L. Chemotherapeutic Drugs: Covalent DNA-Binding Drugs. In: Perry M. Hrsg The Chemotherapy Source Book. Philadelphia: Lippincott Williams and Wilkins; 2001: 169-184
• 6 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
• 7 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
• 8 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
• 9 Roelofs RI, Hrushesky W, Rogin J et al. Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology 1984; 34: 934-938
• 10 Thompson SW, Davis LE, Kornfeld M et al. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer 1984; 54: 1269-1275
• 11 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 European 2002; 13: 229-236
• 12 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
• 13 Gore ME, Fryatt I, Wiltshaw E et al. Cisplatin/carboplatin cross-resistance in ovarian cancer. Br J Cancer 1989; 60: 767-769
• 14 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
• 15 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 Clin Oncol 1988; 24: 1471-1479
• 16 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
• 17 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
• 18 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
• 19 Wilson RH, Lehky T, Thomas RR et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002; 20: 1767-1774
• 20 Sittl R, Lampert A, Huth T et al. Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current. Proc Natl Acad Sci USA 2012; 109: 6704-6709
• 21 Zhao M, Isami K, Nakamura S et al. Acute cold hypersensitivity characteristically induced by oxaliplatin is caused by the enhanced responsiveness of TRPA1 in mice. Molecular Pain 2012; 8: 55
• 22 Krishnan AV, Goldstein D, Friedlander M et al. Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle & Nerve 2005; 32: 51-60
• 23 Johnson IS, Armstrong JG, Gorman M et al. The vinca alkaloids: a new class of oncolytic agents. Cancer Res 1963; 23: 1390-1427
• 24 Rowinsky E, Tolcher A. Chemotherapeutic Drugs: Microtubule-Targeting Drugs. In: Perry M. Hrsg The Chemotherapy Source Book. Philadelphia: Lippincott Williams and Wilkins; 2001: 220-239
• 25 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
• 26 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
• 27 Graf WD, Chance PF, Lensch MW et al. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer 1996; 77: 1356-1362
• 28 Bakshi N, Maselli RA, Gospe Jr SM et al. Fulminant demyelinating neuropathy mimicking cerebral death. Muscle Nerve 1997; 20: 1595-1597
• 29 Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy. A clinical study of fifty leukemic patients. Neurology 1969; 19: 367-374
• 30 Kornblith AB, Anderson J, Cella DF et al. Comparison of psychosocial adaptation and sexual function of survivors of advanced Hodgkin disease treated by MOPP, ABVD, or MOPP alternating with ABVD. Cancer 1992; 70: 2508-2516
• 31 Casey EB, Jellife AM, Le Quesne PM et al. Vincristine neuropathy. Clinical and electrophysiological observations. Brain 1973; 96: 69-86
• 32 Verstappen CC, Koeppen S, Heimans JJ et al. Dose-related vincristine-induced peripheral neuropathy with unexpected off-therapy worsening. Neurology 2005; 64: 1076-1077
• 33 Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979; 277: 665-667
• 34 Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. J Peripher Nerv Syst 2008; 13: 27-46
• 35 Mekhail TM, Markman M. Paclitaxel in cancer therapy. Expert Opin Pharmacother 2002; 3: 755-766
• 36 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
• 37 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
• 38 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
• 39 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
• 40 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
• 41 Postma TJ, Vermorken JB, Liefting AJ et al. Paclitaxel-induced neuropathy. Ann Oncol 1995; 6: 489-494
• 42 Freilich RJ, Balmaceda C, Seidman AD et al. Motor neuropathy due to docetaxel and paclitaxel. Neurology 1996; 47: 115-118
• 43 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
• 44 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
• 45 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
• 46 Jones SE, Erban J, Overmoyer B et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 2005; 23: 5542-5551
• 47 Chan S, Friedrichs K, Noel D et al. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 2341-2354
• 48 Chon HJ, Rha SY, Im CK et al. Docetaxel versus paclitaxel combined with 5-FU and leucovorin in advanced gastric cancer: combined analysis of two phase II trials. Cancer Res Treat 2009; 41: 196-204
• 49 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
• 50 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
• 51 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
• 52 Cata JP, Weng HR, Burton AW et al. Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 2007; 8: 296-306
• 53 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
• 54 Gupta S, Pagliuca A, Devereux S et al. Life-threatening motor neurotoxicity in association with bortezomib. Haematologica 2006; 91: 1001
• 55 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
• 56 Rampen AJ, Jongen JL, van Heuvel I et al. Bortezomib-induced polyneuropathy. Neth J Med 2013; 71: 128-133
• 57 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
• 58 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
• 59 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
• 60 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
• 61 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
• 62 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: 421-427
• 63 Durand JP, Deplanque G, Montheil V et al. Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial. Ann Oncol/ESMO 2012; 23: 200-205
• 64 Pachman DR, Barton DL, Watson JC et al. Chemotherapy-induced peripheral neuropathy: prevention and treatment. Clin Pharmacol Ther 2011; 90: 377-387
• 65 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
• 66 Kautio AL, Haanpaa M, Leminen A et al. Amitriptyline in the prevention of chemotherapy-induced neuropathic symptoms. Anticancer Res 2009; 29: 2601-2606
• 67 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: 2802-2808
• 68 Barton DL, Wos EJ, Qin R et al. A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA. Support care cancer J Multinat 2011; 19: 833-841
• 69 Argyriou AA, Iconomou G, Kalofonos HP. Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 2008; 112: 1593-1599
• 70 Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655
• 71 Trotti A, Colevas AD, Setser A et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003; 13: 176-181
• 72 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: 210-215
• 73 Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207-214
• 74 Mühl H, Pfeilschifter J. Pharmakogenetik und Pharmakogenomik von Methotrexat. Z Rheumatol 2011; 70: 101-107
• 75 Cronstein B, Bertino J. Methotrexate. In: Parnham M, Bruinvels J. Hrsg Milestones in drug therapy. Basel, Boston, Berlin: Birkhäuser; 2000: 1-143
• 76 Posner J. Side effects of chemotherapy. In: Posner J. Hrsg Neurologic complications of cancer. Philadelphia: F.A. Davis; 1995: 282-310
• 77 Glantz MJ, Jaeckle KA, Chamberlain MC et al. A Randomized controlled trial comparing intrathecal sustained-release cytarabin (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors. Clinical Cancer Research 1999; 5: 3394-3402
• 78 Phillips J. Methotrexate toxicity. In: Rottenberg D. Hrsg Neurologic complications of cancer treatment. Boston: Butterworth-Heinmann; 1991: 115-134
• 79 Inaba H, Khan RB, Laningham FH et al. Clinical and radiological characteristics of methotrexate-induced acute encephalopathy in pediatric patients with cancer. Ann Oncol 2008; 19: 178-184
• 80 Dufourg MN, Landman-Parker J, Auclerc MF et al. Age and high-dose methotrexate are associated to clinical acute encephalopathy in FRALLE 93 trial for acute lymphoblastic leukemia in children. Leukemia 2007; 21: 238-247
• 81 Lövblad KO, Kelkar P, Ozdoba C et al. Pure methotrexate encephalopathy presenting with seizures: CT and MRI features. Pediatric Radiology 1998; 28: 86-91
• 82 Mahoney DH, Shuster JJ, Nitschke R et al. Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy – a Pediatric Oncology Group study. J Clinical Oncol 1998; 16: 1712-1722
• 83 Sánchez-Carpintero R, Narbona J, López de Mesa R et al. Transient posterior encephalopathy induced by chemotherapy in children. Pediatr Neurol 2001; 24: 145-148
• 84 Rao RD, Swanson JW, Dejesus RS et al. Methotrexate induced seizures associated with acute reversible magnetic resonance imaging (MRI) changes in a patient with acute lymphoblastic leukemia. Leuk Lymphoma 2002; 43: 1333-1336
• 85 Dicuonzo F, Salvati A, Palma M et al. Posterior reversible encephalopathy syndrome associated with methotrexate neurotoxicity: conventional magnetic resonance and diffusion-weighted imaging findings. J Child Neurol 2009; 24: 1013-1018
• 86 Montour-Proulx I, Kuehn SM, Keene DL et al. Cognitive changes in children treated for acute lymphoblastic leukemia with chemotherapy only according to the Pediatric Oncology Group 9605 protocol. J Child Neurol 2005; 20: 129-133
• 87 Gosavi T, Diong CP, Lim S-H. Methotrexate-induced myelopathy mimicking subacute combined degeneration of the spinal cord. J Clin Neurosci 2013; 20: 1025-1026
• 88 Ackermann R, Semmler A, Maurer GD et al. Methotrexate-induced myelopathy responsive to substitution of multiple folate metabolites. J Neurooncol 2010; 97: 425-427
• 89 Pascual AM, Coret F, Casanova B et al. Anterior lumbosacral polyradiculopathy after intrathecal administration of methotrexate. J Neurol Sciences 2008; 267: 158-161
• 90 Pochedly C. Neurotoxicity due to CNS therapy for leukemia. Med Pediatr Oncol 1977; 3: 101-115
• 91 Clark AW, Cohen SR, Nissenblatt MJ et al. Paraplegia following intrathecal chemotherapy: neuropathologic findings and elevation of myelin basic protein. Cancer 1982; 50: 42-47
• 92 Vagace JM, Caceres-Marzal C, Jimenez M et al. Methotrexate-induced subacute neurotoxicity in a child with acute lymphoblastic leukemia carrying genetic polymorphisms related to folate homeostasis. Am J Hematol 2011; 86: 98-101
• 93 Patterson D, Lee S. Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther 2010; 10: 105-111
• 94 O’Marcaigh AS, Johnson CM, Smithson WA et al. Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin Proc 1996; 71: 161-165
• 95 Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003; 3: 330-338
• 96 Gutheil J, Finucane D. Chemotherapeutic Drugs: Antimetabolites. In: Perry M. Hrsg The Chemotherapy Source Book. Philadelphia: Lippincott Williams and Wilkins; 2001: 185-201
• 97 Koenig H, Patel A. Biochemical basis for fluorouracil neurotoxicity: The role of krebs cycle inhibition by fluoroacetate. Arch Neurol 1970; 23: 155-160
• 98 Riehl JL, Brown WJ. Acute Cerebellar Syndrome Secondary to 5-Fluorouracil Therapy. Neurology 1964; 14 SRC – GoogleScholar 961-967
• 99 Okeda R, Shibutani M, Matsuo T et al. Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning by the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoroβ-alanine. Acta Neuropathologica 1990; 81: 66-73
• 100 Yeh KH, Cheng AL. High-dose 5-fluorouracil infusional therapy is associated with hyperammonaemia, lactic acidosis and encephalopathy. Br J Cancer 1997; 75: 464-465
• 101 Nott L, Price T, Pittman K et al. Hyperammonemia encephalopathy: An important cause of neurological deterioration following chemotherapy. Leukemia & Lymphoma 2007; 48: 1702-1711
• 102 Liaw CC, Wang HM, Wang CH et al. Risk of transient hyperammonemic encephalopathy in cancer patients who received continuous infusion of 5-fluorouracil with the complication of dehydration and infection. Anticancer Drugs 1999; 10: 275-281
• 103 Delval L, Klastersky J. Optic neuropathy in cancer patients. Report of a case possibly related to 5 fluorouracil toxicity and review of the literature. J Neurooncol 2002; 60: 165-169
• 104 Brashear A, Siemers E. Focal dystonia after chemotherapy: a case ­series. J Neurooncol 1997; 34: 163-167
• 105 Bergevin P, Patwardhan V, Weissman J et al. Neurotoxicity of 5-Fluorouracil. Lancet 1975; 305: 410
• 106 Elkiran ET, Altundag K, Beyazit Y et al. Fluorouracil-induced neurotoxicity presenting with generalized tonic-clonic seizure. Ann Pharmacother 2004; 38: 2171
• 107 Bolwell BJ, Cassileth PA, Gale RP. High dose Cytarabin: a review. Leukemia 1988; 2: 253-260
• 108 Patel RS, Rachamalla M, Chary NR et al. Cytarabin induced cerebellar neuronal damage in juvenile rat: correlating neurobehavioral performance with cellular and genetic alterations. Toxicology 2012; 293: 41-52
• 109 Winkelman MD, Hines JD. Cerebellar degeneration caused by high-dose cytosine arabinoside: A clinicopathological study. Ann Neurol 1983; 14: 520-527
• 110 Cole N, Gibson BE. High-dose cytosine arabinoside in the treatment of acute myeloid leukaemia. Blood Reviews 1997; 11: 39-45
• 111 Geller HM, Cheng KY, Goldsmith NK et al. Oxidative stress mediates neuronal DNA damage and apoptosis in response to cytosine arabinoside. J Neurochem 2001; 78: 265-275
• 112 Hwang TL, Yung WK, Estey EH et al. Central nervous system toxicity with high-dose Ara-C. Neurology 1985; 35: 1475-1479
• 113 Chamberlain MC. Neurotoxicity of intra-CSF liposomal Cytarabin (DepoCyt) administered for the treatment of leptomeningeal metastases: a retrospective case series. J Neurooncol 2012; 109: 143-148
• 114 Wen P. Central nervous system complications of cancer therapy. In: Schiff D, Wen P. Hrsg Cancer Neurology in Clinical Practice. Totowa: Humana; 2003: 215-231
• 115 Battipaglia G, Avilia S, Morelli E et al. Posterior reversible encephalopathy syndrome (PRES) during induction chemotherapy for acute myeloblastic leukemia (AML). Ann Hematol 2012; 91: 1327-1328
• 116 Saito B, Nakamaki T, Nakashima H et al. Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose Cytarabin chemotherapy in a patient with acute myeloid leukemia. Am J Hematol 2007; 82: 304-306
• 117 Ostermann K, Pels H, Kowoll A et al. Neurologic complications after intrathecal liposomal Cytarabin in combination with systemic polychemotherapy in primary CNS lymphoma. J Neurooncol 2011; 103: 635-640
• 118 Joseph PJ, Reyes MR. Dorsal column myelopathy following intrathecal chemotherapy for acute lymphoblastic leukemia. J Spinal Cord Med 2013; DOI: 10.1179/2045772312y.0000000081.
• 119 Glantz MJ, LaFollette S, Jaeckle KA et al. Randomized trial of a slow-release versus a standard formulation of cytarabin for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999; 17: 3110-3116
• 120 Bishop J, Matthews J, Young G et al. A randomized study of high-dose Cytarabin in induction in acute myeloid leukemia [see comments]. Blood 1996; 87: 1710-1717
• 121 Stentoft J. The toxicity of Cytarabin. Drug Saf 1990; 5: 7-27
• 122 Nevill TJ, Benstead TJ, McCormick CW et al. Horner’s syndrome and demyelinating peripheral neuropathy caused by high-dose cytosine arabinoside. Am J Hematol 1989; 32: 314-315
• 123 Shaw PJ, Procopis PG, Menser MA et al. Bulbar and pseudobulbar palsy complicating therapy with high-dose cytosine arabinoside in children with leukemia. Med Pediatr Oncol 1991; 19: 122-125
• 124 Jabbour E, O’Brien S, Kantarjian H et al. Neurologic complications associated with intrathecal liposomal Cytarabin given prophylactically in combination with high-dose methotrexate and Cytarabin to pa­tients with acute lymphocytic leukemia. Blood 2007; 109: 3214-3218
• 125 Pranzatelli MR, Mott SH, Pavlakis SG et al. Clinical spectrum of secondary parkinsonism in childhood: a reversible disorder. Pediatr Neurol 1994; 10: 131-140
• 126 Spriggs DR, Stopa E, Mayer RJ et al. Fludarabin Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study. Cancer Research 1986; 46: 5953-5958
• 127 Warrell RP, Berman E. Phase I and II study of Fludarabin phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 1986; 4: 74-79
• 128 Cheson BD, Vena DA, Foss FM et al. Neurotoxicity of purine analogs: a review. J Clin Oncol 1994; 12: 2216-2228
• 129 Lee MS, McKinney AM, Brace JR et al. Clinical and imaging features of fludarabine neurotoxicity. J Neuroophthalmol 2010; 30: 37-41
• 130 Kalita J, Patel NS, Misra UK. Magnetic resonance imaging may simulate progressive multifocal leucoencephalopathy in a patient with chronic lymphocytic leukemia after fludarabine therapy. Ann Indian Acad Neurol 2008; 11: 114-115
• 131 Kiewe P, Seyfert S, Korper S et al. Progressive multifocal leukoencephalopathy with detection of JC virus in a patient with chronic lymphocytic leukemia parallel to onset of fludarabine therapy. Leuk Lymphoma 2003; 44: 1815-1818
• 132 D’Souza A, Wilson J, Mukherjee S et al. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia: a report of three cases and review of the literature. Clin Lymphoma Myeloma Leuk 2010; 10: E1-E9
• 133 Lejniece S, Murovska M, Chapenko S et al. Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient. Exp Oncol 2011; 33: 239-241
• 134 Cohen RB, Abdallah JM, Gray JR et al. Reversible neurologic toxicity in patients treated with standard-dose fludarabine phosphate for mycosis fungoides and chronic lymphocytic leukemia. Ann Intern Med 1993; 118: 114-116
• 135 Nicolao P, Giometto B. Neurological Toxicity of Ifosfamide. Oncology 2003; 65 (Suppl. 02) 11-16
• 136 Küpfer A, Aeschlimann C, Cerny T. Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy. European J Clin Pharmacol 1996; 50: 249-252
• 137 Patel PN. Methylene blue for management of Ifosfamide-induced encephalopathy. Ann Pharmacother 2006; 40: 299-303
• 138 Eeles R, Tait DM, Peckham MJ. Lhermitte’s sign as a complication of cisplatin-containing chemotherapy for testicular cancer. Cancer Treat Rep 1986; 70: 905-907
• 139 Walther PJ, Rossitch Jr. E, Bullard DE. The development of lhermitte’s sign during cisplatin chemotherapy: Possible drug-induced toxicity causing spinal cord demyelination. Cancer 1987; 60: 2170-2172
• 140 Maiese K, Walker RW, Gargan R et al. Intra-arterial cisplatin-associated optic and otic toxicity. Arch Neurol 1992; 49: 83-86
• 141 Connolly RM, Doherty CP, Beddy P et al. Chemotherapy induced reversible posterior leukoencephalopathy syndrome. Lung Cancer 2007; 56: 459-463
• 142 Ito Y, Arahata Y, Goto Y et al. Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome. Am J Neuroradiol 1998; 19: 415-417
• 143 Brauers A, Mattelaer P, Mersdorf A et al. Seizures associated with cisplatin administration. Eur Urol 1997; 32: 118-120
• 144 Li S-H, Chen W-H, Tang Y et al. Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10 963 patients. Clin Neurol Neurosurg 2006; 108: 150-156
• 145 Meattini I, Scotti V, Pescini F et al. Ischemic stroke during cisplatin-based chemotherapy for testicular germ cell tumor: case report and review of the literature. J Chemotherapy 2010; 22: 134-136
• 146 Etgen T, Weidenhofer G, Kubin T. Cisplatin-associated occlusion of the internal carotid artery. Onkologie 2009; 32: 754-757
• 147 Weijl NI, Rutten MFJ, Zwinderman AH et al. Thromboembolic Events During Chemotherapy for Germ Cell Cancer: A Cohort Study and Review of the Literature. J Clin Oncol 2000; 18: 2169-2178
• 148 Dallera F, Gamoletti R, Costa P. Unilateral seizures following vincristine intravenous injection. Tumori 1984; 70: 243-244
• 149 Johnson FL, Bernstein ID, Hartmann JR et al. Seizures associated with vincristine sulfate therapy. J Pediatr 1973; 82: 699-702
• 150 Escuro RS, Adelstein DJ, Carter SG. Syndrome of inappropriate secretion of antidiuretic hormone after infusional vincristine. Cleve Clin J Med 1992; 59: 643-644
• 151 Hualde Olascoaga J, Molins Castiella T, Souto Hernandez S et al. Reversible posterior leukoencephalopathy: report of two cases after vincristine treatment. An Pediatr (Barc) 2008; 68: 282-285
• 152 Ozyurek H, Oguz G, Ozen S et al. Reversible posterior leukoencephalopathy syndrome: report of three cases. J Child Neurol 2005; 20: 990-993
• 153 Hurwitz RL, Mahoney Jr DH, Armstrong DL et al. Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 1988; 16: 216-219
• 154 Boranic M, Raci F. A Parkinson-like syndrome as side effect of chemotherapy with vincristine and adriamycin in a child with acute leukaemia. Biomedicine 1979; 31: 124-125
• 155 Lambrozo J. Intention tremor during chemotherapy with vincristine sulphate. Nouv Presse Med 1979; 8: 3831
• 156 Müller-Tidow C, Krug U, Brunnberg U et al. Tyrosinkinasen als Ziele neuer onkologischer Therapien: Aussichten und Probleme. Dtsch Arztebl International 2007; 104: 1312
• 157 Radford IR. Imatinib. Novartis. Curr Opin Investig Drugs 2002; 3: 492-499
• 158 Guilhot F, Hughes TP, Cortes J et al. Plasma exposure of imatinib and its correlation with clinical response in the tyrosine kinase inhibitor optimization and selectivity trial. Haematologica 2012; 97: 731-738
• 159 Druker BJ, Talpaz M, Resta DJ et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031-1037
• 160 Johnson JR, Bross P, Cohen M et al. Approval Summary: Imatinib mesylate capsules for treatment of adult patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Clinical Cancer Research 2003; 9: 1972-1979
• 161 Kim MS, Lee DH, Lee YR et al. A case of subdural hematoma in pa­tient with chronic myeloid leukemia treated with high-dose imatinib mesylate. Korean J Hematol 2010; 45: 73-75
• 162 Song KW, Rifkind J, Al-Beirouti B et al. Subdural hematomas during CML therapy with imatinib mesylate. Leuk Lymphoma 2004; 45: 1633-1636
• 163 Patel SB, Gojo I, Tidwell ML et al. Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy. Leuk Lymphoma 2011; 52: 1211-1214
• 164 Kane RC, Farrell AT, Madabushi R et al. Sorafenib for the treatment of unresectable hepatocellular carcinoma. Oncologist 2009; 14: 95-100
• 165 Strumberg D, Richly H, Hilger RA et al. Phase I clinical and pharmacokinetic study of the novel raf kinase and vascular endothelial growth factor receptor inhibitor bay 43-9006 in patients with advanced refractory solid tumors. J Clinical Oncology 2005; 23: 965-972
• 166 Laber DA, Mushtaq M. Compassionate use of sorafenib in patients with advanced renal cell cancer. Clin Genitourin Cancer 2009; 7: 34-38
• 167 Govindarajan R, Adusumilli J, Baxter DL et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol 2006; 24: e48
• 168 Dogan E, Aksoy S, Arslan C et al. Probable sorafenib-induced reversible encephalopathy in a patient with hepatocellular carcinoma. Med Oncol 2010; 27: 1436-1437
• 169 Pouessel D, Culine S. High frequency of intracerebral hemorrhage in metastatic renal carcinoma patients with brain metastases treated with tyrosine kinase inhibitors targeting the vascular endothelial growth factor receptor. Eur Urol 2008; 53: 376-381
• 170 Elice F, Jacoub J, Rickles FR et al. Hemostatic complications of angiogenesis inhibitors in cancer patients. Am J Hematol 2008; 83: 862-870
• 171 Je Y, Schutz FAB, Choueiri TK. Risk of bleeding with vascular endothelial growth factor receptor tyrosine-kinase inhibitors sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. Lancet Oncology 2009; 10: 967-974
• 172 Faivre S, Demetri G, Sargent W et al. Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 2007; 6: 734-745
• 173 Zhu AX, Sahani DV, Duda DG et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: A phase II Study. J Clin Oncol 2009; 27: 3027-3035
• 174 Gore ME, Szczylik C, Porta C et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncology 2009; 10: 757-763
• 175 Motl S. Bevacizumab in combination chemotherapy for colorectal and other cancers. Am J Health System Pharm 2005; 62: 1021-1032
• 176 Miller K, Wang M, Gralow J et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: 2666-2676
• 177 Kabbinavar FF, Hambleton J, Mass RD et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 2005; 23: 3706-3712
• 178 Scappaticci FA, Skillings JR, Holden SN et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J National Cancer Institute 2007; 99: 1232-1239
• 179 Tlemsani C, Mir O, Boudou-Rouquette P et al. Posterior reversible encephalopathy syndrome induced by anti-VEGF agents. Target Oncol 2011; 6: 253-258
• 180 Letarte N, Bressler LR, Villano JL. Bevacizumab and central nervous system (CNS) hemorrhage. Cancer Chemother Pharmacol 2013; 71: 1561-1565
• 181 Taugourdeau-Raymond S, Rouby F, Default A et al. Bevacizumab-induced serious side-effects: a review of the French pharmacovigilance database. Eur J Clin Pharmacol 2012; 68: 1103-1107
• 182 Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25: 1539-1544
• 183 Argyriou AA, Assimakopoulos K, Iconomou G et al. Either called “chemobrain” or “chemofog,” the long-term chemotherapy-induced cognitive decline in cancer survivors is real. J Pain Symptom Management 2011; 41: 126-139
• 184 Ferguson R, Ahles T. Chemotherapy associated cognitive impairment in patients with cancer and cancer survivors. Curr Neurol Neurosci Rep 2003; 3: 215-222
• 185 Deeken JF, Löscher W. The blood-brain barrier and cancer: transporters, treatment, and trojan horses. Clin Cancer Res 2007; 13: 1663-1674
• 186 Myers J, Pierce J, Pazdernik T. Neurotoxicology of chemotherapy in relation to cytokine release, the blood-brain barrier, and cognitive impairment. Oncol Nurs Forum 2008; 35: 916-920
• 187 Vardy J, Rourke S, Tannock IF. Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research. J Clin Oncol 2007; 25: 2455-2463
• 188 Vardy J, Wefel JS, Ahles T et al. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Ann Oncol 2008; 19: 623-629
• 189 Taillibert S, Voillery D, Bernard-Marty C. Chemobrain: is systemic chemotherapy neurotoxic?. Curr Opin Oncol 2007; 19: 623-627
• 190 Shilling V, Jenkins V, Trapala IS. The (mis)classification of chemo-fog-methodological inconsistencies in the investigation of cognitive impairment after chemotherapy. Breast Cancer Res Treat 2006; 95: 125-129
• 191 Jansen CE, Dodd MJ, Miaskowski CA et al. Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psychooncology 2008; 17: 1189-1195
• 192 Hermelink K, Untch M, Lux MP et al. Cognitive function during neoadjuvant chemotherapy for breast cancer: results of a prospective, multicenter, longitudinal study. Cancer 2007; 109: 1905-1913
• 193 Ganz PA, Kwan L, Castellon SA et al. Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance. J National Cancer Institute 2013; 105: 791-801
• 194 Correa DD, Root JC, Baser R et al. A prospective evaluation of changes in brain structure and cognitive functions in adult stem cell transplant recipients. Brain Imaging Behav 2013; DOI: 10.1007/s11682-013-9221-8.
• 195 Wefel JS, Lenzi R, Theriault RL et al. The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial. Cancer 2004; 100: 2292-2299
• 196 Wefel JS, Saleeba AK, Buzdar AU et al. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer. Cancer 2010; 116: 3348-3356
• 197 Ahles TA, Saykin AJ, Noll WW et al. The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy. Psychooncology 2003; 12: 612-619
• 198 Hoffmeyer S, Burk O, von Richter O et al. Functional polymorphisms of the human multidrug-resistance gene: Multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 2000; 97: 3473-3478
• 199 McAllister T, Ahles T, Saykin A et al. Cognitive effects of cytotoxic cancer chemotherapy: Predisposing risk factors and potential treatments. Curr Psychiatry Rep 2004; 6: 364-371
• 200 Vardy J, Tannock I. Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol 2007; 63: 183-202
• 201 Schagen SB, Boogerd W, Muller MJ et al. Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer. Acta Oncol 2008; 47: 63-70
• 202 Zeller B, Tamnes CK, Kanellopoulos A et al. Reduced neuroanatomic volumes in long-term survivors of childhood acute lymphoblastic leukemia. J Clin Oncol 2013; 31: 2078-2085
• 203 Bruno J, Hosseini SM, Kesler S. Altered resting state functional brain network topology in chemotherapy-treated breast cancer survivors. Neurobiol Dis 2012; 48: 329-338
• 204 Baudino B, D’Agata F, Caroppo P et al. The chemotherapy long-term effect on cognitive functions and brain metabolism in lymphoma patients. Q J Nucl Med Mol Imaging 2012; 56: 559-568
• 205 Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 2007; 7: 192-201
• 206 Gong X, Schwartz PH, Linskey ME et al. Neural stem/progenitors and glioma stem-like cells have differential sensitivity to chemotherapy. Neurology 2011; 76: 1126-1134