ABSTRACT: Older patients are more susceptible to the complications of chemotherapy, and may be less equipped to react to these complications. After an introduction to the basic principles of geriatric medicine, this article explores the treatment of older cancer patients with systemic chemotherapy, including discussions of the pharmacology of aging, the effectiveness and toxicity of antineoplastic treatment in this population, and issues that need to be addressed in future clinical trials.
Aging is associated with a progressive decline of function, increased prevalence of comorbidity, slower cognition, and progressive sensorial deprivation. Together, these changes lead to decreased functional reserve of multiple organ systems, which influences the pharmacokinetics and pharmacodynamics of drugs. The likelihood of drug interaction increases as well, due to a high prevalence of polypharmacy in these individuals. In addition, aging may be associated with more limited resources and social support.
Older individuals are not only more susceptible to complications of chemotherapy; they are also less equipped to react to these complications. For example, in the absence of a home caregiver, an older patient may not be able to reach the hospital for the management of a severe neutropenic infection, and sometimes may not even be able to reach the phone and call for help. The decision to treat an older individual with cytotoxic drugs should take into account social support.
In this review, we will examine the pharmacokinetics and pharmacodynamics of antineoplastic agents after a brief introduction to geriatric medicine, as a framework of reference for clinical decisions. We will conclude with the outline of a research agenda specific for older cancer patients.
Basic Principles of Geriatrics
This section explores the influence of age on medical decisions in older cancer patients. To this end, it considers the definition of age, its clinical assessment, the goals of cancer treatment in the older aged person, and aging of specific organs and systems.
Definition of Age
lammation, as the accumulation of cellular oxidative damage, as a loss of entropy and “fractality,” and as a loss of the plasticity of tissue stem cells. To a large extent, these definitions represent different faces of the same event and describe interwoven phenomena. The construct of age as chronic inflammation is the most useful from a clinical standpoint, because the inflammatory status of a person may be correlated with life expectancy, function, and the prevalence of typical manifestations of aging called “geriatric syndromes.” Several studies have demonstrated a correlation between the concentration of inflammatory cytokines in the circulation and the risk of death, disability, dementia, delirium, osteoporosis, and failure to thrive.[5,9-12]
Aging is universal but highly individualized. Chronologic age does not reflect physiologic age. Rather, it represents a landmark, located around age 70. That is, the majority of physiologically old individuals are older than 70. This does not mean, however, that all individuals older than 70 are physiologically old. It only means that the determination of physiologic age is indicated for the population aged 70 and over. In addition to age 70, there may be another landmark, between age 90 and 95, beyond which the majority of people are physiologically old. This second landmark has not been clearly identified, however.
Clinical Assessment of Age
Physiologic age is reflected in a person’s independent living, life expectancy, and frailty. Independent living and life expectancy may be estimated with a comprehensive geriatric assessment, or CGA (Table 1). The survival of a person dependent in one or more instrumental activities of daily living (IADLs) depends on someone else compensating for the inability to perform a specific activity, such as a driver who provides transportation or a carrier who brings the groceries home. A person dependent in activities of daily living (ADLs) or with a geriatric syndrome may need a home caregiver or admission to an assisted-living facility.
Function, comorbidity, and geriatric syndromes may be factored in a formula that predicts the 4-year risk of mortality for individuals aged 70 and older.[14,15] Canadian investigators have estimated a person’s physiologic age based on 90 parameters, but this system is too cumbersome for use in a busy clinic. Polypharmacy is both an expression of comorbidity and a risk factor for medication-related complications. Malnutrition may be a sign of inadequate social support or depression, and is itself a risk factor for mortality, functional decline, and therapeutic complications. As already mentioned, social support is essential to the survival and thriving of individuals dependent in one or more IADLs or ADLs.
Functional impairment or disability do not necessarily imply that a person cannot live independently. A functional impairment (eg, weakness of an extremity) becomes a disability when it affects a function (eg, paraplegia may keep a person from walking). Appropriate environmental changes may prevent a disability from becoming a handicap. For example, a paraplegic who has access to a wheelchair may still be independent in transferring.
The construct of frailty has long-term clinical implications. While it is considered germane to aging, frailty still needs a consensus definition. Most gerontologists subscribe to the definition that emerged from a recent conference of experts, who portrayed frailty as a condition of extreme susceptibility to stress. A frail person may lose his or her independence when exposed to a minor stress, such as elective surgery or cytotoxic chemotherapy. The recognition of frailty may play a part in the decision to treat older cancer patients.
Currently, the diagnosis of frailty is based on five criteria derived from the Cardiovascular Health Study (CHS), as outlined in Table 2. The CHS investigators were able to identify three groups of individuals associated with differences in survival duration, risk of hospitalization, and risk of admission to assisted living over an 8-year follow-up period. These three groups were characterized as follows: (1) fit individuals are normal in all parameters; (2) prefrail individuals present with one or two abnormalities; (3) frail individuals present with three or more abnormalities.
The CHS definition represents both an instrument for screening older individuals for frailty, and a frame of reference for future studies of frailty. As an instrument, it is rather rudimentary. While it is very sensitive to frailty, it lacks specificity. After an 8-year follow-up, approximately 60% of the so-called frail individuals and 75% of the prefrail were still alive, and about half of the survivors still enjoyed independent living. This instrument may be fine-tuned by the introduction of additional assessments including, for example, the concentration of inflammatory cytokines in the circulation.
General agreement exists that frailty is a syndrome resulting from multiple pathogeneses, such as chronic inflammation, sarcopenia, loss of organ function, and the combined effect of drugs and comorbidity. A number of important clinical questions must still be addressed, including:
• Is frailty reversible, at least to some extent?
• Is the recognition of frailty useful to identify individuals at risk for specific stresses (eg, surgical procedures or cancer chemotherapy)?
• Can one grade frailty?
• Does frailty affect the course of cancer and other diseases ?
• How does frailty interact with medications?
Goals of Medical Treatment in the Older Person
The definition of physiologic age suggests the scope of treatment goals. In addition to cure, prolongation of survival, and symptom management, other important aims include preservation of independent living (also referred to as maintenance of active life expectancy) and prevention of frailty.
Aging of Specific Organs and Systems
In the same individuals, different organs and systems may age at different rates. These changes may influence the pharmacokinetics and pharmacodynamics of drugs. Common changes of aging include:
• Decreased total body water and total body proteins, and increased total body fat
• Reduction in glomerular filtration rate and tubular function
• Reduction in splanchnic circulation, liver size, and type 1 (cytochrome P450–mediated) hepatic reaction
• Decreased intestinal mucosal surface and ability to regenerate the mucosa after injury; decreased gastric secretions and gastric motility
• Reduced hematopoiesis
• Reduced cardiac reserve
• Reduced brain volume and peripheral nerve conduction
• Reduced production of sexual hormones and growth hormone, and increased production of adrenal steroids and cathecholamines
• Reduced bone density, osteopenia, and osteoporosis.
1. Lichtman SM, Balducci L, Aapro M: Geriatric oncology: A field coming of age. J Clin Oncol 25:1821-1823, 2007.
2. Hurria A, Lichtman SM: Clinical pharmacology of cancer therapies in older adults. Br J Cancer 98:517-522, 2008.
3. O’Mahony D, Gallagher PF: Inappropriate prescribing in the older population: Need for new criteria Age Ageing 37:138-141, 2008.
4. Weitzner MA, Haley WH, Chen H: The family caregiver of the older cancer patient. Hematol Oncol Clin North Am 14:269-281, 2000.
5. Ferrucci L, Corsi A, Lauretani F, et al: The origins of age-related proinflammatory state. Blood 105:2294-2299, 2005.
6. Cai W, He JC, Zhu L, et al: AGE-receptor-1 counteracts cellular oxidant stress induced by AGEs via negative regulation of p66shc-dependent FKHRL1 phosphorylation. Am J Physiol Cell Physiol 294:C145-C152, 2008.
7. Novak V, Hu K, Vyas M, et al: Cardiolocomotor coupling in young and elderly people. J Gerontol A Biol Sci Med Sci 62:86-92, 2007. 8. Edelberg JM, Ballard VL: Stem cell review series: Regulating highly potent stem cells in aging: Environmental influences on plasticity. Aging Cell 7:599-604, 2008.
9. Störk S, Feelders RA, van den Beld AW, et al: Prediction of mortality risk in the elderly. Am J Med 119:519-525, 2006. 10. Cauley JA, Danielson ME, Boudreau AM, et al: Inflammatory markers and incident fracture risk in older men and women: The Health Aging and Body Composition Study. J Bone Miner Res 22:1088-1095, 2007.
11. Schaap LA, Pluijm SM, Deeg JD, et al: Inflammatory markers and loss of muscle mass (sarcopenia) and strength. Am J Med 119:526.e9-e17, 2006.
12. Jefferson AM, Massaro LM, Wolfe PA, et al: Inflammatory biomarkers are associated with total brain volume: The Framingham Heart Study. Neurology 68:1032-1038, 2007.
13. Extermann M, Hurria A: Comprehensive geriatric assessment for older patients with cancer. J Clin Oncol 25:1824-1831, 2007. 14. Lee SJ, Lindquist K, Segal MR, et al: Development and validation of a prognostic index for 4-year mortality in older adults. JAMA 295:801-808, 2006.
15. Carey EC, Covinsky KE, Lui LY, et al: Prediction of mortality in community-living frail elderly people with long-term care needs. J Am Geriatr Soc 56:68-75, 2008.
16. Rockwood K, Mitnitski A, Song X, et al: Long-term risks of death and institutionalization of elderly people in relation to deficit accumulation at age 70. J Am Geriatr Soc 54:975-979, 2006.
17. Andrew MK, Mitnitski MB, Rockwood K: Social vulnerability, frailty and mortality in elderly people. PLoS ONE 3:e2232, 2008.
18. Walston J, Hadley EC, Ferrucci L, et al: Research agenda for frailty in older adults: Toward a better understanding of physiology and etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. J Am Geriatr Soc 54:991-1001, 2006.
19. Fried LP, Tangen CM, Walston J, et al: Frailty in older adults: Evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146-M156, 2001.
20. Leng SX, Xue QL, Tian J, et al: Inflammation and frailty in older women. J Am Geriatr Soc 55:864-871, 2007.
21. Duthie E: Physiologic changes of aging, in Balducci L, Lyman GH, Ershler WB, et al (eds): Comprehensive Geriatric Oncology, 2nd ed. London, Taylor & Francis, 2004.
22. Balducci L, Hardy CL: Hemopoietic stress and age, in Balducci L, Ershler WB, DeGaetano G (eds): Blood Disorders in the Elderly. Cambridge, Cambridge University Press, 2008.
23. Carreca I, Balducci L, Extermann M: Cancer Treatm Rev 32:380-402, 2005.
24. Balducci L: Management of cancer pain in geriatric patients. J Support Oncol 1:175-191, 2003.
25. Kintzel PE, Dorr RT: Anticancer drug renal toxicity and elimination: Dosing guidelines for altered renal function. Cancer Treat Rev 21:33-64, 1995.
26. Marx GM, Blake GM, Galani E, et al: Anticancer drug renal toxicity and elimination: Dosing guidelines for altered renal function. Cancer Treat Rev 21:33-64, 1995.
27. Schrijvers D, Highley M, DeBruyn E, et al: Role of red blood cells in pharmacokinetics of chemotherapeutic agents. Anticancer Drugs 10:147-153, 1999.
28. Extermann M, Chen A, Cantor AB, et al: Predictors of tolerance of chemotherapy in older patients. Eur J Cancer 38:1466-1473, 2002.
29. Bartlett NL, Johnson JL, Wagner-Johnston N, et al: Phase II study of 9-aminocamptothecin in previously treated lymphomas: Results of Cancer and Leukemia Group B 9551. Cancer Chemother Pharmacol Jul 23, 2008 (epub ahead of print).
30. Heider SI, Johnell K, Thorslund M, et al: Trends in polypharmacy and potential drug-drug interactions across educational groups in elderly patients in Sweden for the period 1992-2002. Int J Clin Pharmacol Ther 45:643-653, 2007.
31. Johnell K, Klarin I: The relationship between number of drugs and potential drug-drug interactions in the elderly: A study of over 600,000 elderly patients from the Swedish Prescribed Drug Register. Drug Saf 30:911-918, 2007.
32. Melchert M, Lancet J: Acute myeloid leukemia in the elderly, in Balducci L, Erhsler WB, DeGaetano G (eds): Blood Disorders in the Elderly, pp 237-255. Cambridge, Cambridge University Press, 2008.
33. Vitolo U, Ferreri AJ, Montoto S: Follicular lymphomas.Crit Rev Oncol Hematol 66:248-261, 2008.
34. Campisi J: Aging and cancer cell biology, 2008. Aging Cell 7:281-284, 2008.
35. Alekshun TJ, Alsina M: Multiple myeloma, in Balducci L, Erhsler WB, DeGaetano G (eds): Blood Disorders in the Elderly, pp 272-289. Cambridge, Cambridge University Press, 2008.
36. Daidone MG, Coradini D, Martelli G, et al: Primary breast cancer in elderly women: Biological profile and relation with clinical outcome. Crit Rev Oncol Hematol 45:313-325, 2003.
37. Kuderer NM, Dale DC, Crawford J, 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 25:3158-3167, 2007.
38. Shayne M, Culakova E, Poniewierski MS, et al: Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer 110:1611-1620, 2007.
39. Lyman GH, Kuderer NM: primer in prognostic and predictive models: Development and validation of neutropenia risk models. Support Cancer Ther 2:168-175, 2005.
40. Crawford J, Dale JC, Kuderer NM, et al: Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: The results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 6:109-118, 2008.
41. Lyman GH, Morrison VA, Crawford J, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003.
42. Chrischilles E, Delgado DJ, Stolshek BS, et al: Risk of febrile neutropenia among patients with intermediate-grade non-Hodgkin’s lymphoma receiving CHOP chemotherapy. Leuk Lymphoma 44:2069-2076, 2003.
43. Balducci L, Al Halawani H, Charu V, et al: Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist 12:1416-1424, 2007.
44. Ferrucci L, Balducci L: Anemia of cancer and aging. Semin Oncol. In press.
45. Balducci L, Beghe C: Clinical consequences of anemia, in Balducci L, Ershler WB, DeGaetano G (eds): Blood Disorders in the Elderly. Cambridge, Cambridge University Press, 2008.
46. Balducci L, Aapro: Anemia of aging or anemia and aging, in Balducci L, Ershler WB, Bennett J (eds): Anemia in the Elderly. New York, Springer, 2007.
47. Bennett CL, Silver SM, Djulbegovic B, et al: venous Thrombo-embolism and mortality associated with recombinant erythropoietin and darbepoetin administration in the treatment of cancer associated anemia. JAMA 299:914-924, 2008.
48. Bohlius J, Wilson J, Seidenfeld J, et al: Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708-714, 2006.
49. Peeters K, Stassen JM, Collen D, et al: Emerging treatments for thrombocytopenia: Increasing platelet production. Drug Discov Today 13:798-806, 2008.
50. Sonis ST: Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 5(9 suppl 4):3-11, 2007. 51. Worthington HV, Clarckson, Eden OB: Pathobiology of oral mucositis: Novel insights and opportunities. J Support Oncol 5(9 suppl 4):3-11, 2007.
52. Zuppinger C Timolati F, Suter TM: Pathophysiology and diagnosis of cancer drug induced cardiomyopathy. Cardiovasc Toxicol 7:61-66, 2007.
53. Walker M, Ni O: Neuroprotection during chemotherapy: A systematic review. Am J Clin Oncol 30:82-92, 2007.
54. Gameline L, Boisdron-Celle M, Morel A, et al: Oxaliplatin-related neurotoxicity: Interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol 26:1188-1189, 2008.
55. Holzbeierlein JM, Castle EP, Thrasher JB: Complications of androgen-deprivation therapy for prostate cancer. Clin Prostate Cancer 2:147-152, 2003.
56. Greenspan SL, Brufsky A, Lembersky BC, et al: Risedronate prevents bone loss in breast cancer survivors: A 2-year, randomized, double-blind, placebo-controlled Clinical trial. J Clin Oncol 26:2644-2652, 2008.
57. Brufsky A, Bundred N, Coleman R, et al: Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole. Oncologist 13:503-514, 2008.
58. Smith MR: Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer. Drugs Aging 20:175-183, 2003.
59. Cohen MH, Gootenberg J, Keegan P, et al: FDA drug approval summary: Bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist 12:713-718, 2007.
60. Bouchahda M, Macarulla T, Spano JP, et al: Cetuximab efficacy and safety in a retrospective cohort of elderly patients with heavily pretreated metastatic colorectal cancer. Crit Rev Oncol Hematol 67:255-262, 2008.
61. Schaapveld M, Visser O, Lowman MJ, et al: Risk of new primary nonbreast cancers after breast cancer treatment: A Dutch population-based study. J Clin Oncol 26:1239-1246, 2008.
62. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B experience. J Clin Oncol 25:3699-3704, 2007.
63. Patt DA, Duan Z, Fang S, et al: Acute myeloid leukemia after adjuvant breast cancer therapy in older women: Understanding risk. J Clin Oncol 25:3871-3876, 2007.
64. Hershman D, Neugut AI, Jacobson JS, et al: Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196-205, 2007.
65. LeDeley MC, Suzan F, Cutuli B, et al: Anthracyclines, mitoxantrone, radiotherapy, and granulocyte colony-stimulating factor: Risk factors for leukemia and myelodysplastic syndrome after breast cancer. J Clin Oncol 25:292-300, 2007.
66. Arriola A, Rodriguez-Pinilla SM, Lambros MB, et al: Topoisomerase II alpha amplification may predict benefit from adjuvant anthracyclines in HER2 positive early breast cancer. Breast Cancer Res Treat 106:181-189, 2007.
67. Hequet O, Le OH, Moullet L, et al: Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults. J Clin Oncol 22:1864-1871, 2004.
68. Doyle JJ, Neugut AI, Jacobson JS, et al: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol 23:8597-8605, 2005.
69. Pinder MC, Duan Z, Goodwin JS, et al: Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 25:3808-3815, 2007.
70. Swain SM, Whaley FS, Ewer MS: Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 97:2869-2879, 2003.
71. Balducci L, Cohen HJ, Engtrom P, et al: Senior adult oncology clinical practice guidelines in oncology. J Natl Compr Canc Netw 3:572-590, 2005.