Abstract
Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity.
Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma.
In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents.
The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy.
Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality.
Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.
Similar content being viewed by others
References
Tfayli A, Hentschel P, Madajewicz S, et al. Toxicities related to intraarterial infusion of cisplatin and etoposide in patients with brain tumors. J Neurooncol 1999; 42: 73–7
Boogerd W, Ten Bokkel Huinink WW, Dalesio O, et al. Cisplatin-induced neuropathy: central, peripheral and autonomic nerve involvement. J Neurooncol 1990; 9: 255–63
Lomonaco M, Milone M, Batocchli AP, et al. Cisplatin neuropathy: clinical course and neurophysiological findings. J Neurol 1992; 239: 199–204
Siegal T, Haim N. Cisplatin-induced peripheral neuropathy: frequent off-therapy deterioration, demyelinating syndromes, and muscle cramps. Cancer 1990; 15: 1117–23
Riggs J, Ashraf M, Snyder RD, et al. Prospective nerve conduction studies in cisplatin therapy. Ann Neurol 1988; 23: 92–4
Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol 1992; 10: 795–803
Dewar J, Lunt H, Abernethy DA, et al. Cisplatin neuropathy with Lhermitte’s sign. J Neurol Neurosurg Psychiatry 1986; 49: 96–9
van den Bent MJ, van Putten WL, Hilkens PH, et al. Retreatment with dose-dense weekly cisplatin after previous cisplatin chemotherapy is not complicated by significant neurotoxicity. Eur J Cancer 2002, 91
Gerritsen van der Hoop R, Vecht CJ, van der Burg ME, et al. Prevention of cisplatin neurotoxicity with an ACTH(4–9) analogue in patients with ovarian cancer. N Engl J Med 1990; 322: 89–94
Neijt J, van der Burg M, Vecht C, et al. A double-blind randomized study with Org 2766, an ACTH(4–9) analog, to prevent cisplatin neuropathy [abstract A827]. Proc ASCO 1994; 13: 261
Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled trial. J Clin Oncol 1995; 13: 26–32
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: 2101–12
Rick O, Beyer J, Schwella N, et al. Assessment of amifostine as protection from chemotherapy-induced toxicities after conventional-dose and high-dose chemotherapy in patients with germ cell tumor. Ann Oncol 2001; 12: 1151–5
Gradishar WJ, Stephenson P, Glover DJ, et al. A phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188). Cancer 2001; 92: 2517–22
Riccardi R, Riccardi A, Di Rocco C, et al. Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors. Cancer Chemother Pharmacol 1992; 30: 21–4
O’Brien ME, Tonge K, Blake P, et al. Blindness associated with high-dose carboplatin [letter]. Lancet 1992; 339: 558
Markman M, Kennedy A, Webster K, et al. Neurotoxicity associated with a regimen of carboplatin (AUC 5–6) and paclitaxel (175 mg/m2 over 3 h) employed in the treatment of gynecologic malignancies. J Cancer Res Clin Oncol 2001; 127: 55–8
Cvitkovic E, Bekradda M. Oxaliplatin: a new therapeutic option in colorectal cancer. Semin Oncol 1999; 26: 647–62
Wilson RH, Lehky T, Thomas RR, et al. Acute oxaliplatin-induced peripheral nerve hyperexcitability. J Clin Oncol 2002; 20: 1767–74
Adelsberger H, Quasthoff S, Grosskreutz J, et al. The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 2000; 406: 25–32
Eckel F, Schmelz R, Adelsberger H, et al. Prevention of oxaliplatin-induced neuropathy by carbamazepine: a pilot study. Dtsch Med Wochenschr 2002; 127: 78–82
Focan C, Olivier R, Le Hung S, et al. Neurological toxicity of vindesine used in combination chemotherapy of 51 human solid tumors. Cancer Chemother Pharmacol 1981; 6: 175–81
Romero A, Rabinovich MG, Vallejo CT, et al. Vinorelbine as first-line chemotherapy for metastatic breast carcinoma. J Clin Oncol 1994; 12: 336–41
Bain PG, Lantos PL, Djurovic V, et al. Intrathecal vincristine: a fatal chemotherapeutic error with devastating central nervous system effects. J Neurol 1991; 238: 230–4
Hurwitz RL, Mahoney DH, Armstrong DL, et al. Reversible encephalopathy and seizures as a result of conventional vincristine administration. Med Pediatr Oncol 1988; 16: 216–9
DeAngelis LM, Gnecco C, Taylor L, et al. Evolution of neuropathy and myopathy during intensive vincristine/corticosteroid chemotherapy for non-Hodgkin’s lymphoma. Cancer 1991; 67: 2241–6
Delaney P. Vincristine-induced laryngeal nerve paralysis. Neurology 1982; 32: 1285–8
Sandler SG, Tobin W, Henderson ES. Vincristine-induced neuropathy: a clinical study of fifty leukemic patients. Neurology 1969; 19: 367–74
Lugassy G, Shapira A. Sensorineural hearing loss associated with vincristine treatment. Blut 1990; 61: 320–1
Haim N, Epelbaum R, Ben-Sahar M, et al. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer 1994; 15: 2515–9
McLeod JG, Penny R. Vincristine neuropathy: an electrophysiological and histological study. J Neurol Neurosurg Psychiatry 1969; 32: 297–304
Bradley WG, Lassman LP, Pearce GW, et al. The neuromyopathy of vincristine in man: clinical, electrophysiological and pathological studies. J Neurol Sci 1970; 10: 107–31
Legha SS. Vincristine neurotoxicity, pathophysiology and management. Med Toxicol 1986; 1: 421–7
Postma TJ, Benard BA, Huijgens PC, et al. Long term effects of vincristine on the peripheral nervous system. J Neurooncol 1993; 15: 23–7
Naumann R, Mohm J, Reuner U, et al. Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity. Br J Haematol 2001; 115: 323–5
van Kooten B, van Diemen HA, Groenhout KM, et al. A pilot study on the influence of a corticotropin (4–9) analogue on vinca-alkaloid-induced neuropathy. Arch Neurol 1992; 49: 1027–31
Jackson DV, Wells HB, Atkins JN, et al. Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med 1988; 84: 1016–22
Nieto Y, Cagnoni PJ, Bearman SI, et al. Acute encephalopathy: a new toxicity associated with high dose paclitaxel. Clin Cancer Res 1999; 5: 481–6
Seidman AD, Barrett S. Photopsia during 3-hour paclitaxel administration at doses > 250 mg/m2. J Clin Oncol 1994; 12: 1741–2
van Gerven JM, Moll JW, van den Bent MJ, et al. Paclitaxel (taxol) induces cumulative mild neurotoxicity. Eur J Cancer 1994; 30: 1074–7
Postma TJ, Vermorken JB, Liefting AJ, et al. Paclitaxel-induced neuropathy. Ann Oncol 1995; 6: 489–94
Schiller JH, Storer B, Tutsch K, et al. Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer. J Clin Oncol 1994; 12: 241–8
Freilich RJ, Balmaceda C, Seidman AD, et al. Motor neuropathy due to docetaxel and paclitaxel. Neurology 1996; 47: 115–8
Lorenz E, Hagen B, Himmelmann A, et al. A phase II study of biweekly administration of paclitaxel with recurrent epithelial ovarian cancer. Int J Gynecol Cancer 1999; 9: 373–6
Jerian SM, Sarosy GA, Link CJ, et al. Incapacitating autonomic neuropathy precipitated by Taxol. Gynecol Oncol 1993; 51: 277–80
Sahenk Z, Barohn R, New P, et al. Taxol neuropathy: electrodiagnostic and sural nerve biopsy findings. Arch Neurol 1994; 51: 726–9
Kaplan JG, Einzig AI, Schaumburg HH. Taxol causes permanent large fiber peripheral nerve dysfunction: a lesson for preventative strategies. J Neurooncol 1993; 16: 105–7
Trimble EL, Adams JD, Vena D, et al. Paclitaxel for platinum-refractory ovarian cancer: results from the first 1000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 1993; 11: 2405–10
Lipton RB, Apfel SC, Dutcher JP, et al. Taxol produces a predominantly sensory neuropathy. Neurology 1989; 39: 368–73
Eisenhauer EA, Ten Bokkel Huinink WW, Swenerton KD, et al. European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12: 2654–66
Martoni A, Zamagni C, Gheka A, et al. Antihistamines in the treatment of taxol-induced paroxystic pain syndrome. J Natl Cancer Inst 1993; 85: 676
Apfel SC, Lipton RB, Arezzo JC, et al. Nerve growth factor prevents toxic neuropathy in mice. Ann Neurol 1991; 29: 87–90
Hamers FP, Pette C, Neijt JP, et al. The ACTH(4–9) analog, Org2766 prevents Taxol-induced neuropathy in rats. Eur J Pharmacol 1993b; 233: 177–8
Boyle FM, Wheeler HR, Shenfield GM. Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate. J Neurooncol 1999; 41: 107–16
Vahdat L, Papadopoulos K, Lange D, et al. Reduction of paclitaxel-induced peripheral neuropathy with glutamine. Clin Cancer Res 2001; 7: 1192–7
Di Paola RS, Rodriguez R, Goodin S, et al. Amifostine and dose intense paclitaxel in patients with advanced malignancies. Cancer Ther 1998; 1: 11–7
Gelmon K, Eisenhauer E, Bryce C, et al. Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer. J Clin Oncol 1999; 17: 3038–47
New PZ, Jackson CE, Rinaldi D, et al. Peripheral neuropathy secondary to docetaxel (Taxotere). Neurology 1996; 46: 108–11
Hilkens PH, Verweij J, Stoter G, et al. Peripheral neurotoxicity induced by docetaxel. Neurology 1996; 46: 104–8
Vukelja SJ, Baker WJ, Burris III HA, et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. J Natl Cancer Inst 1993; 85: 1432–3
Mott MG, Stevenson P, Wood CB. Methotrexate meningitis. Lancet 1972; II: 656
Bates S, McKeever P, Masur H, et al. Myelopathy following intrathecal chemotherapy in a patient with extensive Burkitt’s lymphoma and altered immune status. Am J Med 1985; 78: 697–702
Genvresse I, Dietzmann A, Massenkeil G, et al. Subacute encephalopathy after combination chemotherapy including moderate-dose methotrexate in a patient with gastric cancer. Anticancer Drugs 1999; 10: 293–4
Kiu MC, Liaw CC, Yang TS, et al. Transient neurological disturbances induced by the chemotherapy of high-dose methotrexate for osteogenic sarcoma. Anticancer Drugs 1994; 5: 480–2
Blay JY, Conroy T, Chevreau C, et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol 1998; 16: 864–71
Lien HH, Blomlie V, Saeter G, et al. Osteogenic sarcoma: MR signal abnormalities of the brain in asymptomatic patients treated with high-dose methotrexate. Radiology 1991; 179: 547–50
Moore BE, Somers NP, Smith TW. Methotrexate-related non-necrotizing multifocal axonopathy detected by betaamyloid precursor protein immunohistochemistry. Arch Pathol Lab Med 2002; 126: 79–81
Koh S, Nelson Jr MD, Kovanlikaya A, et al. Anterior lumbosacral radiculopathy after intrathecal methotrexate treatment. Pediatr Neurol 1999; 21: 576–8
Ochs J, Mulhern R, Fairclough D, et al. Comparison of neuropsychologic functioning and clinical indicators of neurotoxicity in long-term survivors of childhood leukemia given cranial radiation or parental methotrexate: a prospective study. J Clin Oncol 1991; 9: 145–51
van den Berg H, van der Flier M, van de Wetering MD. Cytarabine-induced aseptic meningitis. Leukemia 2001; 15: 697–9
Dunton SF, Nitschke R, Spruce WE, et al. Progressive ascending paralysis following administration of intrathecal and intravenous cytosine arabinoside: a Pediatric Oncology Group study. Cancer 1986; 57: 1083
Kleinschmidt-DeMasters BK, Yeh M. “Locked-in syndrome” after intrathecal cytosine arabinoside therapy for malignant immunoblastic lymphoma. Cancer 1992; 70: 2504–7
Resar LM, Phillips PC, Kastan MB, et al. Acute neurotoxicity after intrathecal cytosine arabinoside in two adolescents with acute lymphoblastic leukemia of B-cell type. Cancer 1993; 71: 117–23
Herzig RH, Hines JD, Herzig GP. Cerebellar toxicity with high-dose cytosine arabinoside. J Clin Oncol 1987; 5: 927–32
Gottlieb D, Bradstock K, Koutts J, et al. The neurotoxicity of high-dose cytosine arabinoside is age related. Cancer 1987; 60: 1439–41
Ritch PS, Hansen RM, Heuer DK. Ocular toxicity from high-dose cytosine arabinoside. Cancer 1983; 51: 430–2
Shaw PJ, Procopsis PG, Menser MA. Bulbar and pseudobulbar palsy complicating therapy with high-dose cytosine arabinoside in children with leukemia. Med Pediatr Oncol 1991; 19: 122–5
Hoffman DL, Howard JR Jr, Sarma R, et al. Encephalopathy, myelopathy, optic neuropathy, and anosmia associated with intravenous cytosine arabinoside. Clin Neuropharmacol 1993; 16: 258–62
Russell JA, Powles RL. Neuropathy due to cytosine arabinoside. BMJ 1974; 4: 652–3
Powell BL, Capizzi RL, Lyerly ES, et al. Peripheral neuropathy after high-dose cytosine arabinoside, daunorubicin and asparaginase consolidation for acute nonlymphocytic leukemia. J Clin Oncol 1986; 4: 95–7
Scherokman B, Filling-Katz MR, Tell D. Brachial plexus neuropathy following high-dose cytarabine in acute monoblastic leukemia. Cancer Treat Rep 1985; 69: 1005–6
Borgeat A, De Muralt B, Stalder M. Peripheral neuropathy associated with high-dose Ara-C therapy. Cancer 1986; 58: 852–4
Courtney MJ, Coffey ET. The mechanism of ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur J Neurosci 1999; 11: 1073–84
Takimoto CH, Lu ZH, Ahang R, et al. Severe neurotoxicity following 5-fluorouracil-based chemotherapy in a patient with dihydropyrimidine dehydrogenase deficiency. Clin Cancer Res 1996; 2: 477–81
Bixenman WW, Nicholls JV, Warwick OH. Oculomotor disturbances associated with 5-fluorouracil chemotherapy. Am J Ophthalmol 1977; 83: 789–93
Bergevin PR, Patwardhan VC, Weissman J, et al. Neurotoxicity of 5-fluorouracil [letter]. Lancet 1975; I: 410
Howell SB, Pfeifle CE, Wung WE. Effect of allopurinol on the toxicity of high-dose 5-fluorouracil administered by intermittent bolus injection. Cancer 1983; 51: 220–5
Israel ZH, Lossos A, Barak V, et al. Multifocal demyelinative leukoencephalopathy associated with 5-fluorouracil and levamisole. Acta Oncol 2000; 39: 117–20
Saif MW, Wilson RH, Harold N, et al. Peripheral neuropathy associated with weekly oral 5-fluorouracil, leucovorin and eniluracil. Anticancer Drugs 2001; 12: 525–31
DiMaggio JR, Brown R, Baile WF, et al. Hallucinations and ifosfamide-induced neurotoxicity. Cancer 1994; 73: 1509–14
Patel SR, Vadhan-Raj S, Papadopolous N, et al. High-dose ifosfamide in bone and soft tissue sarcoma. Results of phase II and pilot studies: dose-response and schedule dependence. J Clin Oncol 1997; 15: 2378–84
Curtin JP, Koonings PP, Gutierrez M, et al. Ifosfamide-induced neurotoxicity. Gynecol Oncol 1991; 42: 193–6
Pratt CB, Green AA, Horowitz ME, et al. Central nervous system toxicity following the treatment of pediatric patients with ifosfamide/mesna. J Clin Oncol 1986; 4: 1253–61
Pelgrims J, de Vos F, van den Brande J, et al. Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature. Br J Cancer 2000; 82: 291–4
Kende G, Sirkin SR, Thomas PR, et al. Blurring of vision: a previously undescribed complication of cyclophosphamide therapy. Cancer 1979; 44: 69–71
Tashima CK. Immediate cerebral symptoms during rapid intravenous administration of cyclophosphamide (NSC-26271). Cancer Chemother Rep 1975; 59: 441–2
Shingleton BJ, Bienfang DC, Albert DM, et al. Ocular toxicity associated with high-dose carmustine. Arch Ophthalmol 1982; 100: 1766–72
Rosenblum MK, Delattre J-Y, Walker RW, et al. Fatal necrotizing encephalopathy complicating treatment of malignant gliomas with intra-arterial BCNU and irradiation: a pathological study. J Neurooncol 1989; 7: 269–81
Wilson WB, Perez GM, Kleinschmidt-DeMasters BK. Sudden onset of blindness in patients treated with oral CCNU and low-dose cranial irradiation. Cancer 1987; 59: 901–7
Postma TJ, van Groeningen CJ, Witjes RJ, et al. Neurotoxicity of combination chemotherapy with procarbazine, CCNU and vincristine (PCV) for recurrent glioma. J Neurooncol 1998; 38: 69–75
Spivack SD. Procarbazine. Ann Int Med 1974; 81: 795–800
Imrie KR, Couture F, Turner CC, et al. Peripheral neuropathy following high-dose etoposide and autologous bone marrow transplantation. Bone Marrow Transplant 1994; 13: 77–9
Leff RS, Thompson JM, Daly MB, et al. Acute neurologic dysfunction after high-dose etoposide therapy for malignant glioma. Cancer 1988; 62: 32–5
van Dam FS, Schagen SB, Muller MJ, et al. Impairment of cognitive function in women receiving adjuvant treatment for high-risk breast cancer: high-dose versus standard-dose chemotherapy. J Natl Cancer Inst 1998; 90: 210–8
Ahles TA, Saykin AJ, Furstenberg CT, et al. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002; 20: 485–93
Acknowledgements
The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Verstappen, C.C.P., Heimans, J.J., Hoekman, K. et al. Neurotoxic Complications of Chemotherapy in Patients with Cancer. Drugs 63, 1549–1563 (2003). https://doi.org/10.2165/00003495-200363150-00003
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003495-200363150-00003