Secondary Logo

Neurological adverse effects of cancer chemotherapy

Thomas, Adam C.G.

doi: 10.1097/FAD.0b013e32835ed7b5
Original Article

Summary Neurological adverse events can be broadly divided into those affecting the central nervous system and those affecting the peripheral nervous system. Chemotherapy-induced neurological adverse effects can reduce treatment efficacy or lead to treatment failure, and can impair the patient's quality of life. Neurotoxicity is more likely when chemotherapy is combined with radiotherapy. Concomitantly prescribed supportive therapy, and the disease itself, can make it difficult to identify the cause of neurological adverse effects. However, the type and degree of toxicity has been shown to be related to the drug type, dose-intensity and cumulative dosage.

Department of Medical Oncology, University Hospital Antwerp, Edegem, Belgium

Correspondence to Adam C.G. Thomas, MPharm, MRPharmS, IPresc, Dudley Group NHS Foundation Trust, Dudley, West Midlands DY1 2HQ, UK. Tel: +44 13 8424 4311; e-mail:

Editor: R E Ferner, MSc, MD, FRCP, Director of the West Midlands Centre for Adverse Drug Reaction Reporting and Consultant Physician at City Hospital, Birmingham, UK. Assistant Editor: Mr C Anton, MA, MEng. Editorial Board: Australia: Dr M Kennedy, Professor G M Shenfield, Denmark: Professor J S Schou; England: Dr J K Aronson; Netherlands: Professor C J van Boxtel, Dr B H Ch Stricker; New Zealand: Dr T Maling; Scotland: Dr D N Bateman; Wales: Professor P A Routledge.

Back to Top | Article Outline


Improved cancer survival and newer forms of chemotherapy have increased exposure to neurotoxic agents.1 Chemotherapy-induced neurological adverse effects can reduce treatment efficacy because doses are delayed or reduced, and lead to treatment failure (if drugs are contraindicated or refused), surgical intervention, and persistent disability.2–4 The type and degree of this collateral damage depends on the drug, dose-intensity and cumulative dosage.5 It is further affected by the presence of preexisting neurological impairment and baseline neuropathy.6

The impact on activities of daily living (ADLs) is often a critical factor in deciding whether to continue therapy.

Back to Top | Article Outline

Assessing neurological adverse effects

Several toxicity grading systems exist to aid assessment of iatrogenic neurological effects (Table 1), though it is unclear which is best.7–10 National Cancer Institute–Common Toxicity Criteria (NCI-CTC) is used routinely in UK practice, but may not describe the breadth of symptoms.10

Table 1

Table 1

Communicating descriptions of neurotoxicity between care providers can be challenging: for example the same toxicity, ‘severe paraesthesia,’ would be recorded as ‘WHO grade 2’ but ‘NCI-CTC grade 3’. Therefore, it is desirable that the tool adopted by a single provider is consistent and suitably referenced. Nerve conduction studies have limited sensitivity; however, nerve excitability studies are shown to predict patients at risk of neuropathy.11

Confounding factors may make it difficult to establish the cause of neurotoxicity. Peripheral neuropathic pain may, for example, be attributed to the effect of a tumour, as well as prior chemotherapy.12 Cumulative neurological damage occurs with successive cycles of therapy. In addition, cancer pain reportedly affects 48% of patients with early disease and 64–75% of patients with advanced disease.12 One meta-analysis (n = 1647) showed that only a fifth (20.3%) of recorded neuropathic pain was caused by the anticancer therapy.12 It is difficult to detect a change from the previous level of damage using subjective questionnaires.10,11

Back to Top | Article Outline

Central nervous system adverse effects

Central nervous system (CNS) adverse effects range from commonly reported headache to encephalopathy, intracranial haemorrhage (ICH), and the entity known as ‘chemobrain’ (also known as chemohead or chemofog). The differential diagnosis includes progressive disease, cerebrospinal fluid (CSF) obstruction, infectious causes and paraneoplastic syndromes (e.g. hyponatraemia).13

Encephalopathy is defined as an alteration in consciousness, neurobehavioural abnormalities, seizures or focal neurological deficits.13,14 Diffuse encephalopathy is associated with high doses of antimetabolites (therapy such as cytarabine and methotrexate), often in older patients (>60 years) and renal impairment.15–17 Its onset may be acute (within hours) or delayed. In a study of primary CNS lymphomas treated solely with such chemotherapy, 14% of long-term survivors suffered encephalopathy as defined by cognitive decline.16 In 10–15% of treated patients,9,14,17 ifosfamide (an alkylating agent used to treat solid tumours) causes an acute diffuse encephalopathy that is reversible with methylthioninium chloride.17

Posterior reversible encephalopathy syndrome (PRES) is characterized by hypertension, headaches, seizures, confusion/altered mental status and visual disturbance.13,14,18 PRES is well described with ciclosporin, cisplatin, fluoropyrimidine, antiangiogenic therapy and high-dose chemotherapy. PRES is precipitated by acute endothelial cell damage causing a microangiopathy, cerebrovascular dysregulation and vasogenic oedema.13,14,18

Novel inhibitors of angiogenesis such as sunitinib, sorafenib, pazopanib and bevacizumab are known to cause iatrogenic intercranial hypertension (ICH). The risks of ICH, ischaemic stroke, venous thromboembolism and haemorrhage are modestly amplified by such agents. There is also an increased risk of cerebral ischaemia with traditional cytotoxic drugs such as mitomycin, gemcitabine, methotrexate and platinum compounds.14 ICH or stroke may be considered a contraindication to further therapy.13,19,20

‘Chemobrain’ is well documented, specifically in relation to adjuvant treatment of breast cancer, affecting 15–50% of patients.13,21,22 It is a late-onset disorder manifest as a widespread subjective deterioration in executive function (processing, multitasking, goal-directed behaviour) with complaints of forgetfulness and inattentiveness. The current aetiological hypotheses include direct neuronal damage, oxidative stress, DNA damage, induced hormone changes, immune dysregulation/cytokine release and CNS embolism.21 By contrast, a study of patients receiving adjuvant treatment with FOLFOX4 (oxaliplatin, 5-fluorouracil, folinate) to treat colorectal cancer showed no evidence of cognitive decline, but rather changes in emotional performance.23

Back to Top | Article Outline

Peripheral neurological adverse effects

Chemotherapy-induced peripheral neuropathy (CIPN) may involve motor, sensory and autonomic neurons. Clinically, it can present with signs of damage, with or without pain.24 Drugs of different classes cause different patterns of damage. Common causative agents include platinum compounds (oxaliplatin, cisplatin), taxanes (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinorelbine), proteasome inhibitors (bortezomib) and other antineoplastic immunomodulators (ipilimumab, thalidomide and lenalidomide).

Sensory CIPN commonly follows a distal ‘glove and stocking’ distribution.24–26 Effects may include paraesthesia (with or without pain), dysaesthesia, pruritus and proprioceptive loss.24 Bortezomib is associated with small fibre loss, affecting unmyelinated C-fibres,24 whereas platinum compounds such as cisplatin are associated with damage to large fibres and to ganglia.24,27 Paclitaxel therapy is particularly associated with pruritus.28

Pain is an important neurological adverse reaction that is especially associated with early nociceptor loss.24 Improved survival means that long-term supportive management of neuropathic pain is commonly required.

Motor symptoms, for example foot drop, are commonly detected at late progression.24 Effects in the early stages are minor and barely noticeable; for example there may be transient distal cramp. Occasionally, chemotherapy-induced deafferentation causes spontaneous movement disorders.24

Autonomic neurotoxic effects may in rare patients result in symptomatic urinary bladder or sexual dysfunction, constipation and orthostatic hypotension.13,24

Back to Top | Article Outline

Chemotherapy-induced peripheral neuropathy by drug class


Antimetabolites, especially when prescribed at high doses, are more frequently associated with CNS toxicity than with peripheral neuropathy.13,15–17,24 Examples include methotrexate, cytarabine arabinoside (Ara-C) and the closely related agent fludarabine causing encephalopathy and myelopathy.24 Other antimetabolites such as gemcitabine are not known to cause or exacerbate CIPN in combination therapy with taxanes, platinum agents or vinca alkaloids.24,29 5-fluorouracil30 can cause CIPN,31 and in addition a cerebellar syndrome has been described in 2–5% of treated patients. The prodrug of fluorouracil, capecitabine, is known to cause palmoplantar erythrodysaesthesia (PPE), known as ‘hand-foot syndrome,’ in which distal paraesthesia is accompanied by pruritus,24 perhaps as a result of small nerve fibre damage.24,32

Back to Top | Article Outline

Mitotic spindle inhibitors

Vinca alkaloids cause sensori-motor and autonomic neuropathies. Vincristine and vindesine are more potently neurotoxic than vinblastine and vinorelbine.24 A glove-and-stocking pattern of paraesthesia, pain, muscle weakness and cramp with loss of deep-tendon reflexes is common.33 Vinorelbine can produce more severe neurotoxicty in patients previously given paclitaxel therapy.34 The effect is thought to be additive rather than synergistic,24 supporting arguments of overall treatment neurotoxicity.

Constipation is the principal clinical sign of vinca alkaloid-induced autonomic neuropathy. Paralytic ileus or megacolon,24,35 bladder atony, impotence, orthostatic hypotension and arrhythmia may all occur.24 Late-onset vincristine-induced peripheral neuropathy is associated with nine distinct inherited SNPs in the ATP-binding cassette transporter gene (ABCC1). ABBC1 codes for proteins that transport molecules across cell membranes, enhancing cellular penetration. Vincristine is a known substrate of the ABCC1 transporter.36

Neurological adverse effects of taxanes are classically manifest as sensory CIPN.25 Numbness, tingling ‘pins and needles’, burning, reduced or altered sensation with hypoaesthesia/hyperaesthesia and dysaesthesia are all described as characteristic symptoms.24–26 There is a clear cumulative dose-dependence, and susceptibility is amplified by preexisting neuropathy and comorbidity such as diabetes mellitus.25 Docetaxel, when compared with paclitaxel, produces significantly less frequent severe sensory (11% vs. 30%; P < 0.001) and motor (3% vs. 7%; P < 0.001) neuropathy.25

Podophyllin analogues like etoposide prevent mitotic spindle formation through inhibition of topoisomerase. Agents in this group have not been shown to cause CIPN or augment CIPN caused by other agents.24

Back to Top | Article Outline

Platinum agents

Platinum agents show disparate neurotoxic profiles, perhaps because of nucleophile reactivity.37 Ototoxicity (any grade) is reported in 75–100% of patients treated with cisplatin,37 but only 1–2% of patients treated with carboplatin.38 Peripheral neurotoxicity occurs in 15–60% of patients treated with either cisplatin or oxaliplatin, but only 4–6% of patients treated with carboplatin.37,38 Chronic patterns of sensory neuropathy are described in 50% of patients treated with oxaliplatin.37

Platinum compounds are associated with predominantly sensory involvement and damage is linked to the fenestrated capillary blood supply of the sensory neuron.39–42 The concentration of platinum compounds in peripheral nerves is similar to that in tumour tissue,42–45 and causes apoptotic cell death in both.2,38 Delayed onset neuronal damage may be due to ongoing binding of platinum to mitochondrial DNA.46 Sensory neurological adverse effects are dose-limiting and related to total cumulative dosing.27,45,47 Autonomic effects include dizziness, palpitation and impotence.27

Oxaliplatin is also associated with distal cold-induced paraesthesia with or without cramp and laryngopharyngeal dysaethesia. Neurological toxicity (at any grade) occurs in 95% of patients treated.48 The latter may be reduced by prolonged (6 h) infusion protocols.48 One small study (n = 76) demonstrates that repeat oxaliplatin exposure desensitizes the transient receptor potential melastatin-8 (TRPM8), which reduces the cold-sensation detection threshold (CDT), in turn leading to cold-induced oxaliplatin peripheral neurotoxicity.49 These phenomena have been shown to be consistent with cumulative-dose-related functional changes in the dorsal root ganglion.42 Oxaliplatin-induced neurotoxicity may be an axonal neuropathy linked to voltage-gated sodium channels, without significant alteration of the axonal membrane potential or Na+/K+ pump function.42,50,51

Carboplatin is an analogue of cisplatin, which, although less neurotoxic than the other platinum compounds,38 in high doses has a similar profile to cisplatin.52,53 The International Collaborative Ovarian Neoplasm 3 trial showed carboplatin combined with paclitaxel produced moderate-to-severe sensory neuropathy in 20% of patients.54 Another much smaller study (n = 51) demonstrated 85.3% incidence of severe peripheral neuropathy using the same combination in gynaecological malignancy.55

Pharmacogentic studies have shown positive correlations between gene expression, DNA repair and neurotoxicity. The glutathione S-transferase pi-1 gene (GSTP1) codes for enzymes that catalyse conjugation of hydrophobic compounds. A mutation in GSTP1 is associated with increased neurotoxicity from oxaliplatin. The sodium channel, voltage-gated, type 1, alpha subunit gene (SCN1A) codes for proteins in sodium channels that are critical for the cell's ability to transmit electrical signals. The presence of SCN1A is associated with decreased prevalence of neurotoxicity in colorectal cancer treatments.37

Back to Top | Article Outline


Bortezomib is a proteasome inhibitor used to treat multiple myeloma. Case reports suggesting autonomic neuropathy and cardiovascular, gastrointestinal and neuroendocrine dysfunctions have been described.56 Pre-existing CIPN increases the risk of moderate-to-severe bortezomib-induced peripheral neurotoxicity.57 Subcutaneous, rather than intravenous, bortezomib injection reduces the incidence of peripheral neuropathy (all grades) somewhat from 53% to 38% (P = 0.044).58

Additive neuropathy is particularly important in multiple myeloma treatment, as each standard line of therapy carries a prominent risk of CIPN and 15–20% of patients have neuropathy at diagnosis.36 Studies investigating genetic profiles of early-onset and late-onset bortezomib-induced neuropathy describe genes that are associated with drug absorption, distribution, metabolism and excretion are also involved in CIPN.36 Inherited SNPs predict susceptibility to both thalidomide-induced and bortezomib-induced peripheral neuropathy.36

The monoclonal antibody ipilimumab potentiates T-cell activation in the treatment of malignant melanoma. In the pivotal phase-III ‘MDX010–20’ trial (n = 676), one case of fatal Guillain–Barré syndrome is recorded. The product licence identifies severe and life-threatening sensori-motor neuropathies occur in 0.1–1% of treated patients.59 These may include cerebral oedema, cranial neuropathy, peripheral neuropathy, syncope and Guillain–Barré syndrome.59 Case reports describe autonomic neuropathy and an ‘inflammatory enteric neuropathy’.60

Back to Top | Article Outline

Overall treatment neurotoxicity

Each treatment regimen will include the active systemic anticancer therapy (SACT) component and the requisite supportive therapy. Supportive pharmacotherapy is essential in permitting the safe administration of modern dose-intense SACT regimens. It includes premedication (e.g. high-dose corticosteroids), antiemetic, antidiarrhoeal, anti-infective, anticoagulant and antiepileptic treatments. Patients may also be using opioid analgesics to control cancer pain. Some supportive therapy may cause neurological adverse effects or augment the effects of anticancer chemotherapy. CNS toxicity related to supportive therapy, for example corticosteroid-related depression, paranoia and psychosis, can be treatment-limiting.

Aggressive treatment plans involving brain-directed surgery, adjuvant/neoadjuvant cranio-spinal irradiation and prophylactic cranial irradiation after chemotherapy lead to more deleterious consequences.13

Back to Top | Article Outline


Many cancer chemotherapeutic agents can cause serious neurological adverse effects. Serial lines of therapy and multiple treatment modalities expose the patient to greater degrees of neurotoxicity. The overall impact of treatment is important, and should be considered when providing patient information.

Better understanding of genetic susceptibilities, and better tests for monitoring nerve function, could in future help to predict patients at increased risk of CIPN.

Back to Top | Article Outline



Back to Top | Article Outline

Conflicts of interest

None declared.

Back to Top | Article Outline


1. Griffith KA, Merkies ISJ, Hill EE, Cornblath DR. Measures of chemotherapy-induced peripheral neuropathy: a systematic review of psychometric properties. Peripheral Nerve Society 2010; 15:314–325.
2. Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. Journal of Clinical Investigation 1998; 101:2842–2850.
3. Leonard GL, Wright MA, Quinn MG, et al. Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer. BMC Cancer 2005; 5:116–126.
4. Weickhardt A, Wells K, Wells M. Oxaliplatin-induced neuropathy in colorectal cancer. Journal of Oncology, vol. 2011, Article ID 201593, 7 pages, 2011. doi:10.1155/2011/201593.
5. Borsellino N, Bilello A, Spinnato F. Chemotherapy-induced peripheral neurotoxicity: clinical aspects and current therapeutic options. Journal of Supportive Palliative Cancer Care 2008; 4:83–90.
6. Chaudhry V, Chaudhry M, Crawford TO, et al. Toxic neuropathy in patients with preexisting neuropathy. Neurology 2003; 60:337–340.
7. Postma TJ, Heimans JJ, Muller MJ, et al. Pitfalls in grading severity of chemotherapy-induced peripheral neurotoxicity. Annals of Oncology 1998; 9:739–744.
8. Postma TJ, Heimans JJ. Grading of chemotherapy-induced peripheral neuropathy. Annals of Oncology 2000; 11:509–513.
9. Verstappen CC, Heimans JJ, Hoekman K, PostmaTJ. Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management. Drugs 2003; 63:2549–2563.
10. Cavaletti G, Freigeni 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. Journal of the Peripheral Nervous System 2007; 12:210–215.
11. Park SB, Lin CSY, Kiernan MC. Nerve excitability assessment in chemotherapy-induced neurotoxicity. Journal of Visualized Experiments 2012; 62:e3439doi:10.3791/3439.
12. Bennett MI, Rayment C, Hjermstad M, et al. Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 2012; 153:359–365.
13. Chamberlain MC. Neurotoxicity of cancer treatment. Current Oncology Reports 2010; 12:60–67.
14. Schlegel U. Central nervous system toxicity of chemotherapy. European Association NeuroOncology Magazine 2011; 1:25–29.
15. Herzig RH, Hines JD, Herzig GP, et al. Cerebellar toxicity with high-dose cytosine arabinoside. Journal of Clinical Oncology 1987; 5:927–932.
16. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. Journal of Clinical Oncology 1998; 16:859–863.
17. 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. British Journal of Cancer 2000; 82:291–294.
18. Hinchey J, Chaves C, Appignani B, et al. A reversible posterior leukoencephalopathy syndrome. New England Journal of Medicine 1996; 334:494–500.
19. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature Reviews Clinical Oncology 2009; 6:465–477.
20. Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nature Reviews Cancer 2007; 7:475–485.
21. Vardy J, Wefel JS, Ahles T, et al. Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop. Annals of Oncology 2008; 19:623–629.
22. Tannock IF, Ahles TA, Ganz PA, van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. Journal of Clinical Oncology 2004; 22:2233–2239.
23. Andreis F, Ferri M, Mazzochi M, et al. Lack of a chemobrain effect for adjuvant FOLFOX chemotherapy in colon cancer patients. A pilot study. Support Cancer Care 2012: doi 10.1007/s00520-012-1560-2.
24. Windebank AJ, Grisold W. Chemotherapy-induced neuropathy. Journal of the Peripheral Nervous System 2008; 13:27–46.
25. Bhutani M, Colucci PM, Laird-Fick H, Conley BA. Management of paclitaxel-induced neurotoxicity. Oncology Review 2010; 4:107–115.
26. Sorbe B, Graflund M, Nygren L, et al. A phase II study of docetaxel weekly in combination with carboplatin every three weeks as first line chemotherapy in stage IIB-IV epithelial ovarian cancer: neurological toxicity and quality-of-life evaluation. International Journal of Oncology 2011; 40:773–781.
27. Krarup-Hansen A, Fugleholm K, Helweg-Larsen S, et al. Examination of distal involvement in cisplatin-induced neuropathy in man. An electrophysiological and historical study with particular reference to touch receptor function. Brain 1993; 116:1017–1041.
28. Glantz MJ, Choy H, Kearns CM, et al. Phase 1 study of weekly outpatient paclitaxel and concurrent cranial irradiation in adults with astrocytomas. Journal of Clinical Oncology 1996; 14:600–609.
29. Colomer R, Llombart-Cussac A, Lluch A, et al. Biweekly paclitaxel plus gemcitabine in advanced breast cancer: phase II trial and predictive value or HER2 extracellular domain. Annals of Oncology 2004; 15:201–206.
30. Moertel CG, Flemming TR, Macdonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New England Journal of Medicine 1990; 322:352–358.
31. Saif MW, Wilson RH, Harold N, et al. Peripheral neuropathy associated with weekly oral 5-fluorouracil, leucovorin and eniluracil. Anticancer Drugs 2001; 12:525–531.
32. Nagore E, Insa A, Sabnmartin O. Antineoplastic therapy-induced palmer planter erythrodysesthesia (‘hand-foot’) syndrome. Incidence, recognition and management. American Journal of Clinical Dermatology 2000; 1:225–234.
33. DeAngelis LM, Gnecco C, Taylor L, Warrekk RP Jr. Evolution of neuropathy and myopathy during intensive vincristine/corticosteroids chemotherapy for non-Hodgkin's lymphoma. Cancer 1991; 67:2241–2246.
34. Fazeny B, Zifci U, Meryn S, et al. Vinorelbine-induced neurotoxicity in patients with advance breast cancer pretreated with paclitaxel: a phase II study. Cancer Chemotherapy Pharmacology 1996; 39:150–156.
35. Low PA, Vernino S, Suarez G. Autonomic dysfunction in peripheral nerve disease. Muscle Nerve 2003; 27:646–661.
36. Broyl A, Corthals S, Jongen JLM, et al. Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncology 2010; 11:1057–1065.
37. McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Molecular Cancer Therapeutics 2009; 8:10–16.
38. Amptoulach S, Tsavaris N. Neurotoxicity caused by treatment with platinum analogues. Chemotherapy Research and Practice vol. 2011, Article ID 843019, 5 pages, 2011. doi:10.1155/2011/843019.
39. Olsson Y. Studies on vascular permeability in peripheral nerves. IV. Distribution of intravenously injected protein tracers in the peripheral nervous system of various species. Acta Neuopathalogica (Berlin) 1971; 17:114–126.
40. Anzil AP, Blinzinger K, Herrliner H. Fenestrated blood capillaries in rat cranio-spinal sensory ganglia. Cell Tissue Research 1976; 167:563–567.
41. Jacobs JM. Vascular permeability and neurotoxicity. Environmental Health Perspective 1978; 26:107–116.
42. Screnci D, McKeage MJ, Galettis P, et al. Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. British Journal of Cancer 2000; 82:966–972.
43. Krishnan AV, Golstein D, Friedlander M, Kiernan MC. Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle & Nerve 2005; 32:52–60.
44. Thompson SW, Davis LE, Kornfel M, et al. Cisplatin neuropathy. Clinical, electrophysiological, morphologic, and toxologic studies. Cancer 1984; 54:1269–1275.
45. Gregg RW, Molepo JM, Monpetit VJ, et al. Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues and mophologica evidence of toxicity. Journal of Clinical Oncology 1992; 10:795–803.
46. Podratz JL, Schlattau AW, Chen BK, et al. Platinum adduct formation in mitochondrial DNA may underlie the phenomenon of coasting. Journal of the Peripheral Nervous System 2007; 12:69.
47. Fu KK, Kai EFY, Leung CK. Cisplatin neuropathy: a prospective clinical and electrophysiological study in Chinese patients with ovarian carcinoma. Journal of Clinical Pharmacy and Therapeutic 1995; 20:167–172.
48. Summary of product characteristics. Eloxatin (Oxaliplatin) 5 mg/ml concentrate for solution for infusion (Sanofi) 2012. [Accessed 23 November 2012].
49. Kono T, Satomi M, Suno M, et al. Oxaliplatin-induced neurotoxicity involves TRPM8 in the mechanism of acute hypersensitivity to cold sensation. Brain and Behaviour 2012; 2:68–73.
50. Park SB, Lin C S-Y, Krishnan AV, et al. Utilizing natural activity to dissect the pathophysiology of acute oxaliplatin-induced neuropathy. Experimental Neurology 2011; 227:120–127.
51. Park SB, Lin C S-Y, Krishnan AV, et al. Dose effects of oxaliplatin on persistent and transient Na+ conductances and the development of neurotoxicity. PLoS One 2011; 6:e18469.
52. Calvaletti G, Bogliun G, Zincone A, et al. Neuro- and ototoxicity of high-dose carboplatin treatment in poor prognosis ovarian cancer patients. Anticancer Res 1998; 18:3797–3802.
53. Calvaletti G, Fabbrica D, Minoloa C, et al. Annals of Oncology 1998; 9:443–447.
54. International Collaborative Ovarian Neoplasm Group (ICON) 2002. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin and cisplatin in women with ovarian cancer: the ICON 3 randomised trial. Lancet 2002; 360:505–515.
55. Riebandt G, Rodabaugh KJ, Pietkiewicz J, et al. Prospective analysis of chemotherapy-induced neuropathy in patients with gynecologic malignancies. Journal of Clinical Oncology 2011; 29 (suppl; abstr e19737).
56. Stratogianni A, Tosch M, Schlemmer H, et al. Bortezomib-induced severe autonomic neuropathy. Clinical Autonomic Research 2012; 22:199–202.
57. Lanzani F, Mattaveli L, Frigeni B, et al. Role of a preexisting neuropathy on the course of bortezomib-induced peripheral neurotoxicity. Journal of the Peripheral Nervous System 2008; 13:267–274.
58. Summary of product characteristics Yervoy (Iplimumuab) 02/08/2012 (Bristol-Myers Squibb Pharmaceutical Limited) 2012. [Accessed 23 November 2012].
59. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib inpatients with relapsed multiple myeloma: a randomised, phase 3, noninferiority study. Lancet Oncology 2011; 12:431–440.
60. Bhatia S, Huber BR, Upton MP, Thompson JA. Inflammatory enteric neuropathy with severe constipation after treatment for melanoma: a case report. Journal of Immunotherapy 2009; 32:203–305.
© 2013 Lippincott Williams & Wilkins, Inc.