Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 63, Issue 5, pp 761–767 | Cite as

Central and peripheral nervous system toxicity of common chemotherapeutic agents

  • Chrissa Sioka
  • Athanassios P. Kyritsis
Mini Review

Abstract

Central and peripheral nervous system toxicity are frequent complications of most chemotherapy regimens, often leading to reduction of dosages or cessation of the responsible drugs. However, sometimes the afflicted toxicity may not be reversible, especially if it is not recognized early, further compromising the quality of life of the cancer patients. The most common chemotherapeutic agents that might cause CNS toxicity manifested as encephalopathy of various severities include methotrexate, vincristine, ifosfamide, cyclosporine, fludarabine, cytarabine, 5-fluorouracil, cisplatin and the interferons (alpha > beta). Involvement of the peripheral nervous system manifested as distal peripheral neuropathy results after therapy with cisplatin, vincristine, taxanes, suramin and thalidomide. Although several compounds have been proposed as neuroprotective agents, few have been shown to be active against the chemotherapy induced neurotoxicity.

Keywords

Neurotoxicity Chemotherapy Central nervous system Brain Cancer 

References

  1. 1.
    Quasthoff S, Hartung HP (2002) Chemotherapy-induced peripheral neuropathy. J Neurol 249:9–17PubMedCrossRefGoogle Scholar
  2. 2.
    Weng TI, Shih FF, Chen WJ (2004) Unusual causes of hyperammonemia in the ED. Am J Emerg Med 22:105–107PubMedCrossRefGoogle Scholar
  3. 3.
    Dietrich J, Marienhagen J, Schalke B, Bogdahn U, Schlachetzki F (2004) Vascular neurotoxicity following chemotherapy with cisplatin, ifosfamide, and etoposide. Ann Pharmacother 38:242–246PubMedGoogle Scholar
  4. 4.
    Patten SB (2006) Psychiatric side effects of interferon treatment. Curr Drug Saf 1:143–150PubMedCrossRefGoogle Scholar
  5. 5.
    Kovacs A, Szomor A, Abraham I, Nagy F, Losonczy H (2002) Psychiatric sequelae of interferon-alpha therapy. Orv Hetil 143:2183–2187PubMedGoogle Scholar
  6. 6.
    Bannink M, Kruit WH, Van Gool AR, Sleijfer S, van der Holt B, Eggermont AM, Stoter G, Hengeveld MW (2008) Interferon-alpha in oncology patients: fewer psychiatric side effects than anticipated. Psychosomatics 49:56–63PubMedCrossRefGoogle Scholar
  7. 7.
    Meyers CA, Scheibel RS, Forman AD (1991) Persistent neurotoxicity of systemically administered interferon-alpha. Neurology 41:672–676PubMedGoogle Scholar
  8. 8.
    Jaksic W, Veljkovic D, Pozza C, Lewis I (2004) Methotrexate-induced leukoencephalopathy reversed by aminophylline and high-dose folinic acid. Acta Haematol 111:230–232PubMedCrossRefGoogle Scholar
  9. 9.
    Linnebank M, Malessa S, Moskau S, Semmler A, Pels H, Klockgether T, Schlegel U (2007) Acute methotrexate-induced encephalopathy–causal relation to homozygous allelic state for MTR c.2756A>G (D919G)? J Chemother 19:455–457PubMedGoogle Scholar
  10. 10.
    Renard D, Westhovens R, Vandenbussche E, Vandenberghe R (2004) Reversible posterior leucoencephalopathy during oral treatment with methotrexate. J Neurol 251:226–228PubMedCrossRefGoogle Scholar
  11. 11.
    Terasawa Y, Nakane S, Ohnishi T, Harada M, Furutani K, Izumi Y, Kaji R (2007) Case of methotrexate encephalopathy: findings on diffusion tensor image and correlation with clinical outcome. Rinsho Shinkeigaku 47:79–84PubMedGoogle Scholar
  12. 12.
    Eichler AF, Batchelor TT, Henson JW (2007) Diffusion and perfusion imaging in subacute neurotoxicity following high-dose intravenous methotrexate. Neuro Oncol 9:373–377PubMedCrossRefGoogle Scholar
  13. 13.
    Lai R, Abrey LE, Rosenblum MK, DeAngelis LM (2004) Treatment-induced leukoencephalopathy in primary CNS lymphoma: a clinical and autopsy study. Neurology 62:451–456PubMedGoogle Scholar
  14. 14.
    Riga M, Psarommatis I, Korres S, Varvutsi M, Giotakis I, Apostolopoulos N, Ferekidis E (2007) Neurotoxicity of vincristine on the medial olivocochlear bundle. Int J Pediatr Otorhinolaryngol 71:63–69PubMedCrossRefGoogle Scholar
  15. 15.
    Hurwitz RL, Mahoney DH Jr, Armstrong DL, Browder TM (1988) Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 16:216–219PubMedCrossRefGoogle Scholar
  16. 16.
    Toker E, Yenice O, Ogut MS (2004) Isolated abducens nerve palsy induced by vincristine therapy. J AAPOS 8:69–71PubMedCrossRefGoogle Scholar
  17. 17.
    Fleming RA (1997) An overview of cyclophosphamide and ifosfamide pharmacology. Pharmacotherapy 17:146S–154SPubMedGoogle Scholar
  18. 18.
    David KA, Picus J (2005) Evaluating risk factors for the development of ifosfamide encephalopathy. Am J Clin Oncol 28:277–280PubMedCrossRefGoogle Scholar
  19. 19.
    Kilickap S, Cakar M, Onal IK, Tufan A, Akoglu H, Aksoy S, Erman M, Tekuzman G (2006) Nonconvulsive status epilepticus due to ifosfamide. Ann Pharmacother 40:332–335PubMedCrossRefGoogle Scholar
  20. 20.
    Park IS, Lee HJ, Lee YS, Hwang JS, Lee MS (2005) Ifosfamide-induced encephalopathy with or without using methylene blue. Int J Gynecol Cancer 15:807–810PubMedCrossRefGoogle Scholar
  21. 21.
    Dufour C, Grill J, Sabouraud P, Behar C, Munzer M, Motte J, Oberlin O, Paci A, Hartmann O (2006) Ifosfamide induced encephalopathy: 15 observations. Arch Pediatr 13:140–145PubMedCrossRefGoogle Scholar
  22. 22.
    Bartynski WS, Zeigler ZR, Shadduck RK, Lister J (2004) Pretransplantation conditioning influence on the occurrence of cyclosporine or FK–506 neurotoxicity in allogeneic bone marrow transplantation. AJNR Am J Neuroradiol 25:261–269PubMedGoogle Scholar
  23. 23.
    Mueller AR, Platz KP, Bechstein WO, Schattenfroh N, Stoltenburg-Didinger G, Blumhardt G, Christe W, Neuhaus P (1994) Neurotoxicity after orthotopic liver transplantation. A comparison between cyclosporine and FK506. Transplantation 58:155–170PubMedGoogle Scholar
  24. 24.
    Taque S, Peudenier S, Gie S, Rambeau M, Gandemer V, Bridoux L, Betremieux P, De Parscau L, Le Gall E (2004) Central neurotoxicity of cyclosporine in two children with nephrotic syndrome. Pediatr Nephrol 19:276–280PubMedCrossRefGoogle Scholar
  25. 25.
    Teive HA, Brandi IV, Camargo CH, Bittencourt MA, Bonfim CM, Friedrich ML, de Medeiros CR, Werneck LC, Pasquini R (2001) Reversible posterior leucoencephalopathy syndrome associated with bone marrow transplantation. Arq Neuropsiquiatr 59:784–789PubMedGoogle Scholar
  26. 26.
    Cid J, Revilla M, Cervera A, Cervantes F, Munoz E, Ferrer I, Montserrat E (2000) Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia. Ann Hematol 79:392–395PubMedCrossRefGoogle Scholar
  27. 27.
    Saumoy M, Castells G, Escoda L, Mares R, Richart C, Ugarriza A (2002) Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 43:433–436PubMedCrossRefGoogle Scholar
  28. 28.
    Spriggs DR, Stopa E, Mayer RJ, Schoene W, Kufe DW (1986) Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Cancer Res 46:5953–5958PubMedGoogle Scholar
  29. 29.
    Chun HG, Leyland-Jones BR, Caryk SM, Hoth DF (1986) Central nervous system toxicity of fludarabine phosphate. Cancer Treat Rep 70:1225–1228PubMedGoogle Scholar
  30. 30.
    Saito B, Nakamaki T, Nakashima H, Usui T, Hattori N, Kawakami K, Tomoyasu S (2007) Reversible posterior leukoencephalopathy syndrome after repeat intermediate-dose cytarabine chemotherapy in a patient with acute myeloid leukemia. Am J Hematol 82:304–306PubMedCrossRefGoogle Scholar
  31. 31.
    Vaughn DJ, Jarvik JG, Hackney D, Peters S, Stadtmauer EA (1993) High-dose cytarabine neurotoxicity: MR findings during the acute phase. Am J Neuroradiol 14:1014–1016PubMedGoogle Scholar
  32. 32.
    Gottlieb D, Bradstock K, Koutts J, Robertson T, Lee C, Castaldi P (1987) The neurotoxicity of high-dose cytosine arabinoside is age-related. Cancer 60:1439–1441PubMedCrossRefGoogle Scholar
  33. 33.
    Vogel H, Horoupian DS (1993) Filamentous degeneration of neurons. A possible feature of cytosine arabinoside neurotoxicity. Cancer 71:1303–1308PubMedCrossRefGoogle Scholar
  34. 34.
    Lucato LT, McKinney AM, Short J, Teksam M, Truwit CL (2006) Reversible findings of restricted diffusion in 5-fluorouracil neurotoxicity. Australas Radiol 50:364–368PubMedCrossRefGoogle Scholar
  35. 35.
    Takimoto CH, Lu ZH, Zhang R, Liang MD, Larson LV, Cantilena LR Jr, Grem JL, Allegra CJ, Diasio RB, Chu E (1996) Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer Res 2:477–481PubMedGoogle Scholar
  36. 36.
    Barbieux C, Patri B, Cerf I, de Parades V (1996) Acute cerebellar syndrome after treatment with 5-fluorouracil. Bull Cancer 83:77–80PubMedGoogle Scholar
  37. 37.
    Saif MW, Wilson RH, Harold N, Keith B, Dougherty DS, Grem JL (2001) Peripheral neuropathy associated with weekly oral 5-fluorouracil, leucovorin and eniluracil. Anticancer Drugs 12:525–531PubMedCrossRefGoogle Scholar
  38. 38.
    Argyriou AA, Koltzenburg M, Polychronopoulos P, Papapetropoulos S, Kalofonos HP (2008) Peripheral nerve damage associated with administration of taxanes in patients with cancer. Crit Rev Oncol Hematol 66:218–228PubMedCrossRefGoogle Scholar
  39. 39.
    Verstappen CC, Postma TJ, Geldof AA, Heimans JJ (2004) Amifostine protects against chemotherapy-induced neurotoxicity: an in vitro investigation. Anticancer Res 24:2337–2341PubMedGoogle Scholar
  40. 40.
    Openshaw H, Beamon K, Synold TW, Longmate J, Slatkin NE, Doroshow JH, Forman S, Margolin K, Morgan R, Shibata S, Somlo G (2004) Neurophysiological study of peripheral neuropathy after high-dose Paclitaxel: lack of neuroprotective effect of amifostine. Clin Cancer Res 10:461–467PubMedCrossRefGoogle Scholar
  41. 41.
    Argyriou AA, Chroni E, Koutras A, Iconomou G, Papapetropoulos S, Polychronopoulos P, Kalofonos HP (2006) Preventing paclitaxel-induced peripheral neuropathy: a phase II trial of vitamin E supplementation. J Pain Symptom Manage 32:237–244PubMedCrossRefGoogle Scholar
  42. 42.
    Perry JR, Warner E (1996) Transient encephalopathy after paclitaxel (Taxol) infusion. Neurology 46:1596–1599PubMedGoogle Scholar
  43. 43.
    Mayerhofer K, Bodner K, Saletu B, Bodner-Adler B, Anderer P, Hefler L, Kaider A, Leodolter S, Kainz C (2000) Paclitaxel does not cause central nervous adverse effects: a prospective vigilance-controlled EEG mapping study in ovarian cancer patients. Wien Klein Wochenschr 112:1007–1013Google Scholar
  44. 44.
    Ziske CG, Schottker B, Gorschluter M, Mey U, Kleinschmidt R, Schlegel U, Sauerbruch T, Schmidt-Wolf IG (2002) Acute transient encephalopathy after paclitaxel infusion: report of three cases. Ann.Oncol 13:629–631PubMedCrossRefGoogle Scholar
  45. 45.
    von Schlippe M, Fowler CJ, Harland SJ (2001) Cisplatin neurotoxicity in the treatment of metastatic germ cell tumour: time course and prognosis. Br J Cancer 85:823–826CrossRefGoogle Scholar
  46. 46.
    Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, Bove L (2003) Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol 21:927–931PubMedCrossRefGoogle Scholar
  47. 47.
    Leonetti C, Biroccio A, Gabellini C, Scarsella M, Maresca V, Flori E, Bove L, Pace A, Stoppacciaro A, Zupi G, Cognetti F, Picardo M (2003) Alpha-tocopherol protects against cisplatin-induced toxicity without interfering with antitumor efficacy. Int J Cancer 104:243–250PubMedCrossRefGoogle Scholar
  48. 48.
    Bove L, Picardo M, Maresca V, Jandolo B, Pace A (2001) A pilot study on the relation between cisplatin neuropathy and vitamin E. J Exp Clin Cancer Res 20:277–280PubMedGoogle Scholar
  49. 49.
    Ito Y, Arahata Y, Goto Y, Hirayama M, Nagamutsu M, Yasuda T, Yanagi T, Sobue G (1998) Cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome. Am J Neuroradiol 19:415–417PubMedGoogle Scholar
  50. 50.
    Verschraegen C, Conrad CA, Hong WK (1995) Subacute encephalopathic toxicity of cisplatin. Lung Cancer 13:305–309PubMedCrossRefGoogle Scholar
  51. 51.
    Joseph EK, Chen X, Bogen O, Levine JD (2008) Oxaliplatin acts on IB4-positive nociceptors to induce an oxidative stress-dependent acute painful peripheral neuropathy. J Pain 9:463–472PubMedCrossRefGoogle Scholar
  52. 52.
    Hochster HS, Grothey A, Childs BH (2007) Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol 25:4028–4029PubMedCrossRefGoogle Scholar
  53. 53.
    Gamelin L, Boisdron-Celle M, Morel A, Poirier AL, Berger V, Gamelin E, Tournigand C, de Gramont A (2008) Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 26:1188–1189PubMedCrossRefGoogle Scholar
  54. 54.
    Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C (2008) Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer 44:1507–1515PubMedCrossRefGoogle Scholar
  55. 55.
    Plasmati R, Pastorelli F, Cavo M, Petracci E, Zamagni E, Tosi P, Cangini D, Tacchetti P, Salvi F, Bartolomei I, Michelucci R, Tassinari CA (2007) Neuropathy in multiple myeloma treated with thalidomide: a prospective study. Neurology 69:573–581PubMedCrossRefGoogle Scholar
  56. 56.
    Zara G, Ermani M, Rondinone R, Arienti S, Doria A (2008) Thalidomide and sensory neurotoxicity: A neurophysiological study. J.Neurol Neurosurg Psychiatry 79:1258–1261PubMedCrossRefGoogle Scholar
  57. 57.
    Mileshkin L, Stark R, Day B, Seymour JF, Zeldis JB, Prince HM (2006) Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol 24:4507–4514PubMedCrossRefGoogle Scholar
  58. 58.
    Tosi P, Zamagni E, Cellini C, Plasmati R, Cangini D, Tacchetti P, Perrone G, Pastorelli F, Tura S, Baccarani M, Cavo M (2005) Neurological toxicity of long-term (>1 year) thalidomide therapy in patients with multiple myeloma. Eur J Haematol 74:212–216PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Neurosurgical Research InstituteUniversity of IoanninaIoanninaGreece
  2. 2.Department of Nuclear MedicineUniversity Hospital of IoanninaIoanninaGreece
  3. 3.Department of NeurologyUniversity of Ioannina School of MedicineIoanninaGreece

Personalised recommendations