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Pharmacology of Chemotherapy

  • Christopher B. SteerEmail author
  • Gabriel W. H. Mak
Chapter

Abstract

Chemotherapy is a key component of treatment of women with epithelial ovarian cancer regardless of age. Increasing comorbidities and changes in drug pharmacodynamics and pharmacokinetics with increasing age can lead to increased toxicity. The assessment of renal function is vital for accurate dosing of renally excreted agents such as carboplatin. While data from clinical trials specifically in older adults is limited, data from subgroups of elderly patients informs clinicians of the utility and toxicity profiles of chemotherapy. The pharmacological characteristics of the commonly used chemotherapeutic agents are further explored.

Keywords

Pharmacology Chemotherapy Elderly patients Comorbidity Renal function 

References

  1. 1.
    Ania BJ, Suman VJ, et al. Incidence of anemia in older people: an epidemiologic study in a well defined population. J Am Geriatr Soc. 1997;45(7):825–31.PubMedGoogle Scholar
  2. 2.
    Armstrong DK. Topotecan dosing guidelines in ovarian cancer: reduction and management of hematologic toxicity. Oncologist. 2004;9(1):33–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Balducci L. Pharmacology of antineoplastic medications in older cancer patients. Oncology. 2009;23(1):78–85.PubMedGoogle Scholar
  4. 4.
    Baraldi-Junkins CA, Beck AC, et al. Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am. 2000;14(1):45–61, viii.PubMedCrossRefGoogle Scholar
  5. 5.
    Bennett CL, Silver SM, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299(8):914–24.PubMedCrossRefGoogle Scholar
  6. 6.
    Blaney SM, Cole DE, et al. Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates. Cancer Res. 1993;53(4):725–7.PubMedGoogle Scholar
  7. 7.
    Bohlius J, Schmidlin K, et al. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373(9674):1532–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Bouchardy C, Rapiti E, et al. Older female cancer patients: importance, causes, and consequences of undertreatment. J Clin Oncol. 2007;25(14):1858–69.PubMedCrossRefGoogle Scholar
  9. 9.
    Bruno R, Vivier N, et al. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel. Invest New Drugs. 2001;19(2):163–9.PubMedCrossRefGoogle Scholar
  10. 10.
    Cashman J, Wright J, et al. The treatment of co-morbidities in older patients with metastatic cancer. Support Care Cancer. 2010;18(5):651–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Cattel L, Ceruti M, et al. From conventional to stealth liposomes: a new Frontier in cancer chemotherapy. J Chemother. 2004;16 Suppl 4:94–7.PubMedGoogle Scholar
  12. 12.
    Ceccaroni M, D’Agostino G, et al. Gynecological malignancies in elderly patients: is age 70 a limit to standard-dose chemotherapy? An Italian retrospective toxicity multicentric study. Gynecol Oncol. 2002;85(3):445–50.PubMedCrossRefGoogle Scholar
  13. 13.
    Coleman R. The use of bisphosphonates in cancer treatment. Ann N Y Acad Sci. 2011;1218:3–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Coleman RE, McCloskey EV. Bisphosphonates in oncology. Bone. 2011;49(1):71–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Davila E, Gardner LB. Clinical value of the creatinine clearance before the administration of chemotherapy with cisplatin. Cancer. 1987;60(2):161–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Durnas C, Loi CM, et al. Hepatic drug metabolism and aging. Clin Pharmacokinet. 1990;19(5):359–89.PubMedCrossRefGoogle Scholar
  17. 17.
    Efstathiou E, Dimopoulos MA, et al. Advanced epithelial ovarian cancer in the elderly: ­chemotherapy tolerance and outcome. Anticancer Res. 2007;27(1B):611–7.PubMedGoogle Scholar
  18. 18.
    Eisenhauer EL, Tew WP, et al. Response and outcomes in elderly patients with stages IIIC-IV ovarian cancer receiving platinum-taxane chemotherapy. Gynecol Oncol. 2007;106(2):381–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments: what the cardiologist needs to know. Nat Rev Cardiol. 2010;7(10):564–75.PubMedCrossRefGoogle Scholar
  20. 20.
    Extermann M. Basic assessment of the older cancer patient. Curr Treat Options Oncol. 2011;12(3):276–85.PubMedCrossRefGoogle Scholar
  21. 21.
    Extermann M, Chen H, et al. Predictors of tolerance to chemotherapy in older cancer patients: a prospective pilot study. Eur J Cancer. 2002;38(11):1466–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Extermann M, Hurria A. Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol. 2007;25(14):1824–31.PubMedCrossRefGoogle Scholar
  23. 23.
    Ferrero JM, Weber B, et al. Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial. Ann Oncol. 2007;18(2):263–8.PubMedCrossRefGoogle Scholar
  24. 24.
    Fidias P, Supko JG, et al. A phase II study of weekly paclitaxel in elderly patients with advanced non-small cell lung cancer. Clin Cancer Res. 2001;7(12):3942–9.PubMedGoogle Scholar
  25. 25.
    Gillison TL, Chatta GS. Cancer chemotherapy in the elderly patient. Oncology. 2010;24(1):76–85.PubMedGoogle Scholar
  26. 26.
    Girre V, Arkoub H, et al. Potential drug interactions in elderly cancer patients. Crit Rev Oncol Hematol. 2011;78(3):220–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Hanigan MH, Dela Cruz BL, et al. Use of prescription and nonprescription medications and supplements by cancer patients during chemotherapy: questionnaire validation. J Oncol Pharm Pract. 2008;14(3):123–30.PubMedCrossRefGoogle Scholar
  28. 28.
    Hilpert F, du Bois A, et al. Feasibility, toxicity and quality of life of first-line chemotherapy with platinum/paclitaxel in elderly patients aged >=70 years with advanced ovarian cancer–a study by the AGO OVAR Germany. Ann Oncol. 2006;18(2):282–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Hurria A. Embracing the complexity of comorbidity. J Clin Oncol. 2011;29(32):4217–8.Google Scholar
  30. 30.
    Hurria A, Lichtman SM. Pharmacokinetics of chemotherapy in the older patient. Cancer Control. 2007;14(1):32–43.PubMedGoogle Scholar
  31. 31.
    Hurria A, Lichtman SM. Clinical pharmacology of cancer therapies in older adults. Br J Cancer. 2008;98(3):517–22.PubMedCrossRefGoogle Scholar
  32. 32.
    Hutchins L, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med. 1999;341(27):2061–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Jain L, Figg WDP. Polypharmacy in view of advances in cancer treatment. Oncology. 2008;22(9):1055, 1058, 1060.Google Scholar
  34. 34.
    Klotz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metab Rev. 2009;41(2):67–76.PubMedCrossRefGoogle Scholar
  35. 35.
    Kuderer NM, Dale DC, et al. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving ­chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158–67.PubMedCrossRefGoogle Scholar
  36. 36.
    Kumar Pal S, Katheria V, et al. Evaluating the older patient with cancer: understanding frailty and the geriatric assessment. CA Cancer J Clin. 2010;60(2):120–32.CrossRefGoogle Scholar
  37. 37.
    Kurtz JE, Kaminsky MC, et al. Ovarian cancer in elderly patients: carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in late relapse: a Gynecologic Cancer Intergroup (GCIG) CALYPSO sub-study. Ann Oncol. 2011;22(11):2417–23.PubMedCrossRefGoogle Scholar
  38. 38.
    Launay-Vacher V, Chatelut E, et al. Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol. 2007;18(8):1314–21.PubMedCrossRefGoogle Scholar
  39. 39.
    Lee L, Cheung WY, et al. Impact of comorbidity on chemotherapy use and outcomes in solid tumors: a systematic review. J Clin Oncol. 2010;29(1):106–17.PubMedCrossRefGoogle Scholar
  40. 40.
    Lees J, Chan A. Polypharmacy in elderly patients with cancer: clinical implications and ­management. Lancet Oncol. 2011;12:1249–57.PubMedCrossRefGoogle Scholar
  41. 41.
    Lichtman SM, Hollis D, et al. Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762). J Clin Oncol. 2006;24(12):1846–51.PubMedCrossRefGoogle Scholar
  42. 42.
    Lichtman SM, Wildiers H, et al. International society of geriatric oncology chemotherapy taskforce: evaluation of chemotherapy in older patients – an analysis of the medical literature. J Clin Oncol. 2007;25(14):1832–43.PubMedCrossRefGoogle Scholar
  43. 43.
    Lichtman SM, Wildiers H, et al. International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer. 2007;43(1):14–34.PubMedCrossRefGoogle Scholar
  44. 44.
    Lichtman SM. Older patients and the shifting focus of cancer care. Oncology. 2009;23(1):86, 88.PubMedGoogle Scholar
  45. 45.
    Lindeman RD, Tobin J, et al. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33(4):278–85.PubMedGoogle Scholar
  46. 46.
    Lindeman RD, Tobin JD, et al. Association between blood pressure and the rate of decline in renal function with age. Kidney Int. 1984;26(6):861–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Lorusso D, Pietragalla A, et al. Review role of topotecan in gynaecological cancers: current indications and perspectives. Crit Rev Oncol Hematol. 2010;74(3):163–74.PubMedCrossRefGoogle Scholar
  48. 48.
    Maas HA, Janssen-Heijnen ML, et al. Comprehensive geriatric assessment and its clinical impact in oncology. Eur J Cancer. 2007;43(15):2161–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Marx GM. Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients. Ann Oncol. 2004;15(2):291–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Misra D, Seo PH, et al. Aging and cancer. Clin Adv Hematol Oncol. 2004;2(7):457–65.PubMedGoogle Scholar
  51. 51.
    Morotti M, Valenzano Menada M, et al. Pharmacokinetic and toxicity considerations for the use of anthracyclines in ovarian cancer treatment. Expert Opin Drug Metab Toxicol. 2011;7(6):707–20.PubMedCrossRefGoogle Scholar
  52. 52.
    Pageau SC. Denosumab. MAbs. 2009;1(3):210–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Saf. 2000;22(4):263–302.PubMedCrossRefGoogle Scholar
  54. 54.
    Pal SK, Hurria A. Impact of age, sex, and comorbidity on cancer therapy and disease progression. J Clin Oncol. 2010;28(26):4086–93.PubMedCrossRefGoogle Scholar
  55. 55.
    Pallis AG, Ring A, et al. EORTC workshop on clinical trial methodology in older individuals with a diagnosis of solid tumors. Ann Oncol. 2011;22(8):1922–6.PubMedCrossRefGoogle Scholar
  56. 56.
    Parmar MKB, Adams M, et al. Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer. Lancet. 2002;360(9332):505–15.CrossRefGoogle Scholar
  57. 57.
    Pignata S, Scambia G, et al. Carboplatin and pegylated liposomal doxorubicin for advanced ovarian cancer: preliminary activity results of the MITO-2 phase III trial. Oncology. 2008;76(1):49–54.PubMedCrossRefGoogle Scholar
  58. 58.
    Piver MS. 21st Century challenge of ovarian cancer in the elderly. A personal perspective. Oncology. 2008;22(14):1580–5.PubMedGoogle Scholar
  59. 59.
    Puts MT, Costa-Lima B, et al. Medication problems in older, newly diagnosed cancer patients in Canada: how common are they? A prospective pilot study. Drugs Aging. 2009;26(6):519–36.PubMedCrossRefGoogle Scholar
  60. 60.
    Rao AV, Hurria A, et al. Geriatric oncology: past, present, future. J Oncol Pract. 2008;4(4):190–2.PubMedCrossRefGoogle Scholar
  61. 61.
    Repetto L, Audisio RA. Elderly patients have become the leading drug consumers: it’s high time to properly evaluate new drugs within the real targeted population. J Clin Oncol. 2006;24(35):e62–3.PubMedCrossRefGoogle Scholar
  62. 62.
    Rizzo JD, Brouwers M, et al. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010;28(33):4996–5010.PubMedCrossRefGoogle Scholar
  63. 63.
    Rodin MB, Mohile SG. A practical approach to geriatric assessment in oncology. J Clin Oncol. 2007;25(14):1936–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Safra T. Cardiac safety of liposomal anthracyclines. Oncologist. 2003;8 Suppl 2:17–24.PubMedCrossRefGoogle Scholar
  65. 65.
    Sawhney R, Sehl M, et al. Physiologic aspects of aging: impact on cancer management and decision making, part I. Cancer J. 2005;11(6):449–60.PubMedCrossRefGoogle Scholar
  66. 66.
    Schutte W, Manegold C, et al. Topotecan – a new treatment option in the therapy of brain metastases of lung cancer. Front Radiat Ther Oncol. 1999;33:354–63.PubMedCrossRefGoogle Scholar
  67. 67.
    Scripture CD, Sparreboom A, et al. Modulation of cytochrome P450 activity: implications for cancer therapy. Lancet Oncol. 2005;6(10):780–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Sehl M, Sawhney R, et al. Physiologic aspects of aging: impact on cancer management and decision making, part II. Cancer J. 2005;11(6):461–73.PubMedCrossRefGoogle Scholar
  69. 69.
    Shepherd FA, Abratt RP, et al. Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol. 1997;24(2 Suppl 7):S7–50–55.Google Scholar
  70. 70.
    Shi S, Klotz U. Age-related changes in pharmacokinetics. Curr Drug Metab. 2011;12:601–10.PubMedCrossRefGoogle Scholar
  71. 71.
    Smorenburg CH, ten Tije AJ, et al. Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur J Cancer. 2003;39(2):196–202.PubMedCrossRefGoogle Scholar
  72. 72.
    Sokol KC, Knudsen JF, et al. Polypharmacy in older oncology patients and the need for an interdisciplinary approach to side-effect management. J Clin Pharm Ther. 2007;32(2):169–75.PubMedCrossRefGoogle Scholar
  73. 73.
    Sparreboom A. Comparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in cremophor (taxol). Clin Cancer Res. 2005;11(11):4136–43.PubMedCrossRefGoogle Scholar
  74. 74.
    Sparreboom A, van Tellingen O, et al. Nonlinear pharmacokinetics of paclitaxel in mice results from the pharmaceutical vehicle cremophor EL. Cancer Res. 1996;56(9):2112–5.PubMedGoogle Scholar
  75. 75.
    Steer CB. Chemotherapy for ovarian cancer in the older adult. Curr Treat Options Oncol. 2009;10(3–4):159–70.PubMedCrossRefGoogle Scholar
  76. 76.
    Stein BN, Petrelli NJ, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial. Cancer. 1995;75(1):11–7.PubMedCrossRefGoogle Scholar
  77. 77.
    Swedko PJ, Clark HD, et al. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med. 2003;163(3):356–60.PubMedCrossRefGoogle Scholar
  78. 78.
    Tam-McDevitt J. Polypharmacy, aging, and cancer. Oncology. 2008;22(9):1052–5.PubMedGoogle Scholar
  79. 79.
    Tew WP, Lichtman SM. Ovarian cancer in older women. Semin Oncol. 2008;35(6):582–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Tredan O, Geay JF, et al. Carboplatin/cyclophosphamide or carboplatin/paclitaxel in elderly patients with advanced ovarian cancer? Analysis of two consecutive trials from the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. Ann Oncol. 2007;18(2):256–62.PubMedCrossRefGoogle Scholar
  81. 81.
    Venook AP, Egorin MJ, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol. 2000;18(14):2780–7.PubMedGoogle Scholar
  82. 82.
    Vestal RE. Aging and pharmacology. Cancer. 1997;80(7):1302–10.PubMedCrossRefGoogle Scholar
  83. 83.
    Villella JA, Chaudhry T, et al. Comparison of tolerance of combination carboplatin and paclitaxel chemotherapy by age in women with ovarian cancer. Gynecol Oncol. 2002;86(3):316–22.PubMedCrossRefGoogle Scholar
  84. 84.
    Walker M, Ni O. Neuroprotection during chemotherapy: a systematic review. Am J Clin Oncol. 2007;30(1):82–92.PubMedCrossRefGoogle Scholar
  85. 85.
    Wasil T, Lichtman SM. Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. Oncologist. 2005;10(8):602–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Werneke U, Earl J, et al. Potential health risks of complementary alternative medicines in cancer patients. Br J Cancer. 2004;90(2):408–13.PubMedCrossRefGoogle Scholar
  87. 87.
    Wildiers H. Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer. 2007;43(15):2235–41.PubMedCrossRefGoogle Scholar
  88. 88.
    Wong A, Soo RA, et al. Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metab Rev. 2009;41(2):77–88.PubMedCrossRefGoogle Scholar
  89. 89.
    Woodle MC, Lasic DD. Sterically stabilized liposomes. Biochim Biophys Acta. 1992;1113(2):171–99.PubMedCrossRefGoogle Scholar
  90. 90.
    Wright JG, Boddy AV, et al. Estimation of glomerular filtration rate in cancer patients. Br J Cancer. 2001;84(4):452–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Wright JD, Doan T, et al. Variability in chemotherapy delivery for elderly women with advanced stage ovarian cancer and its impact on survival. Br J Cancer. 2008;98(7):1197–203.PubMedCrossRefGoogle Scholar
  92. 92.
    Yancik R. Cancer burden in the aged: an epidemiologic and demographic overview. Cancer. 1997;80(7):1273–83.PubMedCrossRefGoogle Scholar
  93. 93.
    Zuppinger C, Timolati F, et al. Pathophysiology and diagnosis of cancer drug induced ­cardiomyopathy. Cardiovasc Toxicol. 2007;7(2):61–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.Border Medical OncologyWodongaAustralia

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