Chemo Fog pp 96-112

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 678)

Evaluation of Multiple Neurotoxic Outcomes in Cancer Chemotherapy

  • Bernard Weiss


Although it is now clear that cognitive dysfunction is a common accompaniment of cancer chemotherapy, its implications await further research and direction. Most of the clinical research relies on standard neuropsychological tests that were developed to diagnose stable traits. Cognitive dysfunction in patients undergoing treatment varies with time, however. Its dimensions will vary during the course of treatment, which generally consists of cycles of drug administration followed by recovery periods. To effectively determine the connection between chemotherapy and cognitive function requires neuropsychological tests based on performance, so that they can be administered repeatedly at specified times during the entire course of treatment and beyond. A number of computerized test batteries, many of which have been developed for environmental neurotoxicology, are now available that fit such criteria. Moreover, cognitive impairment is only one aspect of chemotherapy-induced neurotoxicity. A full appreciation of its scope requires assessment of sensory functions such as vision, audition and somatosensory properties and assessment of motor function. A program of research based on animal models is also essential. Only with animal models is it possible to determine dose-response relationships and to couple behavioral with mechanistic indices such as neuroplasticity. Animal behavior models play a vital role in environmental toxicology because, from them, it is possible to derive some index of exposure that limits adverse effects. However, as in human testing, it is critical to choose situations whose properties remain stable over long periods of time so as to trace the time course of neurotoxicity. Schedule-controlled operant behavior offers the most promising source of animal models.


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  1. 1.
    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(17):2455–2463.PubMedCrossRefGoogle Scholar
  2. 2.
    Taillibert S, Voillery D, Bernard-Marty C. Chemobrain: Is systemic chemotherapy neurotoxic? Curr Opin Oncol 2007; 19(6):623–627.PubMedCrossRefGoogle Scholar
  3. 3.
    Ahles TA, Saykin AJ. Candidate mechanisms for chemotherapy-induced cognitive changes. Nat Rev Cancer 2007; 7(3):192–201.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Hess LM, Insel KC. Chemotherapy-related change in cognitive function: A conceptual model. Oncol Nurs Forum 2007; 34(5):981–994.PubMedCrossRefGoogle Scholar
  5. 5.
    Brown MS, Stemmer SM, Simon JH et al. White matter disease induced by high-dose chemotherapy: Longitudinal study with MR imaging and proton spectroscopy. AJNR Am J Neuroradiol 1998; 19(2):217–221.PubMedGoogle Scholar
  6. 6.
    Silverman DH, Dy CJ, Castellon SA et al. Altered frontocortical, cerebellar and basal ganglia activity in adjuvant-treated breast cancer survivors 5-10 years after chemotherapy. Breast Cancer Res Treat 2007; 103(3):303–311.PubMedCrossRefGoogle Scholar
  7. 7.
    Inagaki M, Yoshikawa E, Matsuoka Y et al. Smaller regional volumes of brain gray and white matter demonstrated in breast cancer survivors exposed to adjuvant chemotherapy. Cancer 2007; 109(1):146–156.PubMedCrossRefGoogle Scholar
  8. 8.
    Schiff D, Wen P. Central nervous system toxicity from cancer therapies. Hematol Oncol Clin North Am 2006; 20(6):1377–1398.PubMedCrossRefGoogle Scholar
  9. 9.
    Duffner PK. The long term effects of chemotherapy on the central nervous system. J Biol 2006; 5(7):21.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Dietrich J, Han R, Yang Y et al. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 2006; 5(7):22.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Weiss B, Laties VG, eds. Behavioral Toxicology. New York: Plenum, 1975.Google Scholar
  12. 12.
    Wefel JS, Kayl AE, Meyers CA. Neuropsychological dysfunction associated with cancer and cancer therapies: A conceptual review of an emerging target. Br J Cancer 2004; 90(9):1691–1696.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Hanninen H. The psychological performance profile in occupational intoxications. Neurotoxicol Teratol 1988; 10(5):485–488.PubMedCrossRefGoogle Scholar
  14. 14.
    Wetherell A. Performance tests. Environ Health Perspect 1996; 104(Suppl 2):247–273.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Slikker W Jr, Beck BD, Cory-Slechta DA et al. Cognitive tests: Interpretation for neurotoxicity? (workshop summary). Toxicol Sci 2000; 58(2):222–234.PubMedCrossRefGoogle Scholar
  16. 16.
    Fray PJ, Robbins TW. CANTAB battery: Proposed utility in neurotoxicology. Neurotoxicol Teratol 1996; 18(4):499–504.PubMedCrossRefGoogle Scholar
  17. 17.
    Rohlman DS, Gimenes LS, Eckerman DA et al. Development of the behavioral assessment and research system (BARS) to detect and characterize neurotoxicity in humans. Neurotoxicology 2003; 24(4–5):523–531.PubMedCrossRefGoogle Scholar
  18. 18.
    Rohlman DS, Lasarev M, Anger WK et al. Neurobehavioral performance of adult and adolescent agricultural workers. Neurotoxicology 2007; 28(2):374–380.PubMedCrossRefGoogle Scholar
  19. 19.
    Blackwell AD, Sahakian BJ, Vesey R et al. Detecting dementia: Novel neuropsychological markers of preclinical Alzheimer’s disease. Dement Geriatr Cogn Disord 2004; 17(1–2):42–48.PubMedCrossRefGoogle Scholar
  20. 20.
    Schmid KE, Kornek GV, Scheithauer W et al. Update on ocular complications of systemic cancer chemotherapy. Surv Ophthalmol 2006; 51(1):19–40.PubMedCrossRefGoogle Scholar
  21. 21.
    Eisner A, Incognito LJ. The color appearance of stimuli detected via short-wavelength-sensitive cones for breast cancer survivors using tamoxifen. Vision Res 2006; 46(11):1816–1822.PubMedCrossRefGoogle Scholar
  22. 22.
    Iregren A, Andersson M, Nylen P. Color vision and occupational chemical exposures: I. an overview of tests and effects. Neurotoxicology 2002; 23(6):719–733.PubMedCrossRefGoogle Scholar
  23. 23.
    Haymes SA, Roberts KF, Cruess AF et al. The letter contrast sensitivity test: Clinical evaluation of a new design. Invest Ophthalmol Vis Sci 2006; 47(6):2739–2745.PubMedCrossRefGoogle Scholar
  24. 24.
    Schreiber JS, Hudnell HK, Geller AM et al. Apartment residents’ and day care workers’ exposures to tetrachloroethylene and deficits in visual contrast sensitivity. Environ Health Perspect 2002; 110(7):655–664.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Rademaker-Lakhai JM, Crul M, Zuur L et al. Relationship between cisplatin administration and the development of ototoxicity. J Clin Oncol 2006; 24(6):918–924.PubMedCrossRefGoogle Scholar
  26. 26.
    Cavaletti G, Bogliun G, Marzorati L et al. Grading of chemotherapy-induced peripheral neurotoxicity using the total neuropathy scale. Neurology 2003; 61(9):1297–1300.PubMedCrossRefGoogle Scholar
  27. 27.
    Postma TJ, Aaronson NK, Heimans JJ et al. The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: The QLQ-CIPN20. Eur J Cancer 2005; 41(8):1135–1139.PubMedCrossRefGoogle Scholar
  28. 28.
    Maurissen JPJ, Weiss B. Vibration sensitivity as an index of somato-sensory function in monkeys and humans. In: Spencer PS, Schaumberg HH, ed. Experimental and Clinical Neurotoxicology. New York: Williams and Wilkins, 1980.Google Scholar
  29. 29.
    Tremblay F, Mireault AC, Dessureault L et al. Postural stabilization from fingertip contact II. relationships between age, tactile sensibility and magnitude of contact forces. Exp Brain Res 2005; 164(2):155–164.PubMedCrossRefGoogle Scholar
  30. 30.
    Ravasco P. Aspects of taste and compliance in patients with cancer. Eur J Oncol Nurs 2005; 9(Suppl 2): S84–91.CrossRefGoogle Scholar
  31. 31.
    Antunes MB, Bowler R, Doty RL. San Francisco/Oakland bay bridge welder study: Olfactory function. Neurology 2007; 69(12):1278–1284.PubMedCrossRefGoogle Scholar
  32. 32.
    Ellingsen DG, Bast-Pettersen R, Efskind J et al. Neuropsychological effects of low mercury vapor exposure in chloralkali workers. Neurotoxicology 2001; 22(2):249–258.PubMedCrossRefGoogle Scholar
  33. 33.
    Bleecker ML, Ford DP, Vaughan CG et al. The association of lead exposure and motor performance mediated by cerebral white matter change. Neurotoxicology 2007; 28(2):318–323.PubMedCrossRefGoogle Scholar
  34. 34.
    Wastensson G, Lamoureux D, Sallsten G et al. Quantitative assessment of neuromotor function in workers with current low exposure to mercury vapor. Neurotoxicology 2008; 29(4):596–604.PubMedCrossRefGoogle Scholar
  35. 35.
    Tannock IF, Ahles TA, Ganz PA et al. Cognitive impairment associated with chemotherapy for cancer: Report of a workshop. J Clin Oncol 2004; 22(11):2233–2239.PubMedCrossRefGoogle Scholar
  36. 36.
    Lee GD, Longo DL, Wang Y et al. Transient improvement in cognitive function and synaptic plasticity in rats following cancer chemotherapy. Clin Cancer Res 2006; 12(1):198–205.PubMedCrossRefGoogle Scholar
  37. 37.
    Seigers R, Schagen SB, Beerling W et al. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res 2008; 186(2):168–175.PubMedCrossRefGoogle Scholar
  38. 38.
    Foley JJ, Raffa RB, Walker EA. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Psychopharmacology (Berl) 2008; 199(4):527–538.CrossRefGoogle Scholar
  39. 39.
    Konat GW, Kraszpulski M, James I et al. Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis 2008; 23(3):325–333.PubMedCrossRefGoogle Scholar
  40. 40.
    Mustafa S, Walker A, Bennett G et al. 5-fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 2008; 28(2):323–330.PubMedCrossRefGoogle Scholar
  41. 41.
    Winocur G, Vardy J, Binns MA et al. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav 2006; 85(1):66–75.PubMedCrossRefGoogle Scholar
  42. 42.
    Han R, Yang YM, Dietrich J et al. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol 2008; 7(4):12.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    McArthur HL, Hudis CA. Advances in adjuvant chemotherapy of early stage breast cancer. Cancer Treat Res 2008; 141:37–53.PubMedCrossRefGoogle Scholar
  44. 44.
    Kreukels BP, van Dam FS, Ridderinkhof KR et al. Persistent neurocognitive problems after adjuvant chemotherapy for breast cancer. Clin Breast Cancer 2008; 8(1):80–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Castellon SA, Ganz PA, Bower JE et al. Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen. J Clin Exp Neuropsychol 2004; 26(7):955–969.PubMedCrossRefGoogle Scholar
  46. 46.
    Rugo HS, Ahles T. The impact of adjuvant therapy for breast cancer on cognitive function: Current evidence and directions for research. Semin Oncol 2003; 30(6):749–762.PubMedCrossRefGoogle Scholar
  47. 47.
    Weiss B. Chemobrain: A translational challenge for neurotoxicology. Neurotoxicology 2008; 29(5):891–898.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Winsauer PJ, Quinton MS, Porter JR et al. Effects of MDMA administration on scopolamine-induced disruptions of learning and performance in rats. Pharmacol Biochem Behav 2004; 79(3):459–472.PubMedCrossRefGoogle Scholar
  49. 49.
    Cory-Slechta DA, Pokora MJ, Widzowski DV. Behavioral manifestations of prolonged lead exposure initiated at different stages of the life cycle: II. delayed spatial alternation. Neurotoxicology 1991; 12(4):761–776.PubMedGoogle Scholar
  50. 50.
    Newland MC, Reile PA, Langston JL. Gestational exposure to methylmercury retards choice in transition in aging rats. Neurotoxicol Teratol 2004; 26(2):179–194.PubMedCrossRefGoogle Scholar
  51. 51.
    Hurria A, Rosen C, Hudis C et al. Cognitive function of older patients receiving adjuvant chemotherapy for breast cancer: A pilot prospective longitudinal study. J Am Geriatr Soc 2006; 54(6):925–931.PubMedCrossRefGoogle Scholar
  52. 52.
    Markowski VP, Cox C, Preston R et al. Impaired cued delayed alternation behavior in adult rat offspring following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on gestation day 15. Neurotoxicol Teratol 2002; 24(2):209–218.PubMedCrossRefGoogle Scholar
  53. 53.
    Weiss B, Stern S, Cox C et al. Perinatal and lifetime exposure to methylmercury in the mouse: Behavioral effects. Neurotoxicology 2005; 26(4):675–690.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Bernard Weiss
    • 1
  1. 1.Weiss-University of Rochester School of Medicine and DentistryRochesterUSA

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