The number of individuals aged 65 years and older is growing rapidly, and the majority of cancers are diagnosed in this age group. Age-related changes in physiology can affect chemotherapy pharmacokinetics and pharmacodynamics in older patients.
Methods
We review the literature regarding the impact of age on the pharmacokinetics of commonly used chemotherapy drugs and discuss age-related changes in physiology and pharmacology that can affect chemotherapy tolerance in older patients.
Results
The data on age-related changes in chemotherapy pharmacokinetics are conflicting. While a few studies report age-related differences in chemotherapy pharmacokinetics, most found no significant difference or subtle differences in pharmacokinetics with aging. A difference in pharmacodynamics was commonly seen, however, with older patients at increased risk of myelosuppression and toxicity from age-related decline in organ function. The majority of these studies were performed in a small cohort of patients, thus limiting the generalizability of these results.
Conclusions
Additional studies are needed to address the pharmacokinetics and pharmacodynamics of cancer therapies in the older patient. Multicenter pharmacokinetic studies of adequate sample size, which include a thorough evaluation of physiologic factors and geriatric assessment parameters, would provide further insight into the factors affecting treatment tolerance. These studies would also help to guide appropriate chemotherapy dosing and interventions in order to maximize efficacy and minimize toxicity in the older patient.
References
1.
YancikR.. Cancer burden in the aged: an epidemiologic and demographic overview.Cancer.1997; 80: 1273–1283.
2.
YancikR., RiesL.A.. Aging and cancer in America: demographic and epidemiologic perspectives.Hematol Oncol Clin North Am.2000; 14: 17–23.
3.
HutchinsL.F., UngerJ.M., CrowleyJ.J.. Underrepresentation of patients 65 years of age or older in cancer- treatment trials.N Engl J Med.1999; 341: 2061–2067.
4.
YeeK.W., PaterJ.L., PhoL.. Enrollment of older patients in cancer treatment trials in Canada: why is age a barrier?J Clin Oncol.2003; 21: 1618–1623.
5.
TrimbleE.L., CarterC.L., CainD.. Representation of older patients in cancer treatment trials.Cancer.1994; 74(suppl 7): 2208–2214.
6.
TalaricoL., ChenG., PazdurR.. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration.J Clin Oncol.2004; 22: 4626–4631. Erratum in: J Clin Oncol. 2004; 22: 4811.
7.
KemenyM.M., PetersonB.L., KornblithA.B.. Barriers to clinical trial participation by older women with breast cancer.J Clin Oncol.2003; 21: 2268–2275.
8.
NewcombP.A., CarboneP.P.. Cancer treatment and age: patient perspectives.J Natl Cancer Inst.1993; 85: 1580–1584.
9.
MussH.B., WoolfS., BerryD.. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer.JAMA.2005; 293: 1073–1081.
10.
ChristmanK., MussH.B., CaseL.D.. Chemotherapy of metastatic breast cancer in the elderly. The Piedmont Oncology Association experience.JAMA.1992; 268: 57–62.
11.
Giovanazzi-BannonS., RademakerA., LaiG.. Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study.J Clin Oncol.1994; 12: 2447–2452.
12.
IbrahimN.K., FryeD.K., BuzdarA.U.. Doxorubicin-based chemotherapy in elderly patients with metastatic breast cancer. Tolerance and outcome.Arch Intern Med.1996; 156: 882–888.
13.
CrivellariD., BonettiM., Castiglione-GertschM.. Burdens and benefits of adjuvant cyclophosphamide, methotrexate, and fluorouracil and tamoxifen for elderly patients with breast cancer: the International Breast Cancer Study Group Trial VII.J Clin Oncol.2000; 18: 1412–1422.
14.
MonfardiniS., AversaS.M., ZoliV.. Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin's lymphomas.Ann Oncol.2005; 16: 1352–1358. Epub 2005 Apr 27.
15.
LilenbaumR.C., HerndonJEII, ListM.A.. Single-agent versus combination chemotherapy in advanced nonsmall-cell lung cancer: the cancer and leukemia group B (study 9730).J Clin Oncol.2005; 23: 190–196.
16.
SawhneyR., SehlM., NaeimA.. Physiologic aspects of aging: impact on cancer management and decision making, part I.Cancer J.2005; 11: 449–460.
17.
SehlM., SawhneyR., NaeimA.. Physiologic aspects of aging: impact on cancer management and decision making, part II.Cancer J.2005; 11: 461–473.
18.
DuthieE.D.. Physiology of aging: relevance to symptom perception and treatment tolerance. In: BalducciL., LymanG.H., ErshlerW.B., eds. Comprehensive Geriatric Oncology.2nd ed.London; New York: Taylor & Francis; 2004.
19.
YuenG.J.. Altered pharmacokinetics in the elderly.Clin Geriatr Med.1990; 6: 257–267.
20.
BakerS.D., GrochowL.B.. Pharmacology of cancer chemotherapy in the older person.Clin Geriatr Med.1997; 13: 169–183.
21.
KastrissiosH., BlaschkeT.F.. Medication compliance as a feature in drug development.Annu Rev Pharmacol Toxicol.1997; 37: 451–475.
22.
VestalR.E.. Aging and pharmacology.Cancer.1997; 80: 1302–1310.
23.
AvornJ., GurwitzJ.H.. Principles of pharmacology. In CasselC.K., CohenH.J., LarsonE.B., eds. Geriatric Medicine.3rd ed.New York: Springer-Verlag; 1996.
24.
BakerS.D., van SchaikR.H., RivoryL.P.. Factors affecting cytochrome P-450 3A activity in cancer patients.Clin Cancer Res.2004; 10: 8341–8350.
25.
HuntC.M., WesterkamW.R., StaveG.M.. Effect of age and gender on the activity of human hepatic CYP3A.Biochem Pharmacol.1992; 44: 275–283.
26.
SchwartzJ.B.. Race but not age affects erythromycin breath test results in older hypertensive men.J Clin Pharmacol.2001; 41: 324–329.
27.
SotaniemiE.A., ArrantoA.J., PelkonenO.. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions.Clin Pharmacol Ther.1997; 61: 331–339.
28.
EvansW.E., McLeodH.L.. Pharmacogenomics-drug disposition, drug targets, and side effects.N Engl J Med.2003; 348: 538–549.
29.
FlockhartD.A., RaeJ.M.. Cytochrome P450 3A pharmacogenetics: the road that needs traveled.Pharmacogenomics J.2003; 3: 3–5.
30.
LindemanR.D., TobinJ., ShockN.W.. Longitudinal studies on the rate of decline in renal function with age.J Am Geriatr Soc.1985; 33: 278–285.
31.
Fehrman-EkholmI., SkeppholmL.. Renal function in the elderly (>70 years old) measured by means of iohexol clearance, serum creatinine, serum urea and estimated clearance.Scand J Urol Nephrol.2004; 38: 73–77.
32.
CockcroftD.W., GaultM.H.. Prediction of creatinine clearance from serum creatinine.Nephron.1976; 16: 31–41.
33.
JelliffeR.W.. Estimation of creatinine clearance when urine cannot be collected.Lancet.1971; 1: 975–976.
34.
RimonE., KaganskyN., CojocaruL.. Can creatinine clearance be accurately predicted by formulae in octogenarian in-patients?QJM.2004; 97: 281–287.
35.
BurkhardtH., BojarskyG., GretzN.. Creatinine clearance, Cockcroft-Gault formula and cystatin C: estimators of true glomerular filtration rate in the elderly?Gerontology.2002; 48: 140–146.
36.
MarxG.M., BlakeG.M., GalaniE.. Evaluation of the Cockroft-Gault, Jelliffe and Wright formulae in estimating renal function in elderly cancer patients.Ann Oncol.2004; 15: 291–295.
37.
LeveyA.S., BoschJ.P., LewisJ.B.. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group.Ann Intern Med.1999; 130: 461–470.
38.
KintzelP.E., DorrR.T.. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function.Cancer Treat Rev.1995; 21: 33–64.
39.
GandhiT.K., WeingartS.N., BorusJ.. Adverse drug events in ambulatory care.N Engl J Med.2003; 348: 1556–1564.
40.
DelafuenteJ.C.. Understanding and preventing drug interactions in elderly patients.Crit Rev Oncol Hematol.2003; 48: 133–143.
41.
HanlonJ.T., PieperC.F., HajjarE.R.. Incidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay.J Gerontol A Biol Sci Med Sci.2006; 61: 511–515.
42.
ZhanC., SanglJ., BiermanA.S.. Potentially inappropriate medication use in the community-dwelling elderly: findings from the 1996 Medical Expenditure Panel Survey.JAMA.2001; 286: 2823–2829.
43.
LichtmanS.M., HollisD., MillerA.A.. Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762).J Clin Oncol.2006; 24: 1846–1851.
44.
FidiasP., SupkoJ.G., MartinsR.. A phase II study of weekly paclitaxel in elderly patients with advanced nonsmall cell lung cancer.Clin Cancer Res.2001; 7: 3942–3949.
45.
SmorenburgC.H., ten TijeA.J., VerweijJ.. Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer.Eur J Cancer.2003; 39: 196–202.
46.
BrunoR., VivierN., Veyrat-FolletC.. Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships for docetaxel.Invest New Drugs.2001; 19: 163–169.
47.
ten TijeA.J., VerweijJ., CarducciM.A.. Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the elderly.J Clin Oncol.2005; 23: 1070–1077.
48.
SlavieroK.A., ClarkeS.J., McLachlanA.J.. Population pharmacokinetics of weekly docetaxel in patients with advanced cancer.Br J Clin Pharmacol.2004; 57: 44–53.
49.
HurriaA., FlemmingM., BakerS.D.. Pharmacokinetics and toxicity of weekly docetaxel in the elderly.Clin Cancer Res. In press, 2006.
50.
MinamiH., OheY., NihoS.. Comparison of pharmacokinetics and pharmacodynamics of docetaxel and Cisplatin in elderly and non-elderly patients: why is toxicity increased in elderly patients?J Clin Oncol.2004; 22: 2901–2908.
51.
RobieuxI., SorioR., BorsattiE.. Pharmacokinetics of vinorelbine in patients with liver metastases.Clin Pharmacol Ther.1996; 59: 32–40.
52.
SorioR., RobieuxI., GalligioniE.. Pharmacokinetics and tolerance of vinorelbine in elderly patients with metastatic breast cancer.Eur J Cancer.1997; 33: 301–303.
53.
GauvinA., PinguetF., CulineS., Astre,. Bayesian estimate of vinorelbine pharmacokinetic parameters in elderly patients with advanced metastatic cancer.Clin Cancer Res.2000; 6: 2690–2695.
54.
MilanoG., EtienneM.C., Cassuto-ViguierE.. Influence of sex and age on fluorouracil clearance.J Clin Oncol.1992; 10: 1171–1175.
55.
SteinB.N., PetrelliN.J., DouglassH.O.. Age and sex are independent predictors of 5-fluorouracil toxicity. Analysis of a large scale phase III trial.Cancer.1995; 75: 11–17.
56.
SloanJ.A., GoldbergR.M., SargentD.J.. Women experience greater toxicity with fluorouracil-based chemotherapy for colorectal cancer.J Clin Oncol.2002; 20: 1491–1498.
57.
PopescuR.A., NormanA., RossP.J.. Adjuvant or palliative chemotherapy for colorectal cancer in patients 70 years or older.J Clin Oncol.1999; 17: 2412–2418.
58.
ChiaraS., NobileM.T., VincentiM.. Advanced colorectal cancer in the elderly: results of consecutive trials with 5-fluorouracil-based chemotherapy.Cancer Chemother Pharmacol.1998; 42: 336–340.
59.
SargentD.J., GoldbergR.M., JacobsonS.D.. A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.N Engl J Med.2001; 345: 1091–1097.
60.
CassidyJ., TwelvesC., CameronD.. Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients.Cancer Chemother Pharmacol.1999; 44: 453–460.
61.
PooleC., GardinerJ., TwelvesC.. Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients.Cancer Chemother Pharmacol.2002; 49: 225–234. Epub 2002 Jan 10. Epub 2005 Feb 14.
62.
BajettaE., ProcopioG., CelioL.. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women.J Clin Oncol.2005; 23: 2155–2161.
63.
CamidgeR., ReignerB., CassidyJ.. Significant effect of capecitabine on the pharmacokinetics and pharmacodynamics of warfarin in patients with cancer.J Clin Oncol.2005; 23: 4719–4725.
64.
SharmaR., RivoryL., BealeP.. A phase II study of fixed-dose capecitabine and assessment of predictors of toxicity in patients with advanced/metastatic colorectal cancer.Br J Cancer.2006; 94: 964–968.
65.
BressolleF., BolognaC., KinowskiJ.M.. Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis. A comparison with young patients.J Rheumatol.1997; 24: 1903–1909.
66.
BressolleF., BolognaC., KinowskiJ.M.. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients.Ann Rheum Dis.1998; 57: 110–113.
67.
GelmanR.S., TaylorSGIV. Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance.J Clin Oncol.1984; 2: 1404–1413.
RubinE.H., AndersenJ.W., BergD.T.. Risk factors for high-dose cytarabine neurotoxicity: an analysis of a Cancer and Leukemia Group B trial in patients with acute myeloid leukemia.J Clin Oncol.1992; 10: 948–953.
70.
SmithG.A., DamonL.E., RugoH.S.. High-dose cytarabine dose modification reduces the incidence of neurotoxicity in patients with renal insufficiency.J Clin Oncol.1997; 15: 833–839.
71.
SlevinM.L.. The clinical pharmacology of etoposide.Cancer.1991; 67(suppl 1): 319–329.
72.
ToffoliG., CoronaG., SorioR.. Population pharmacokinetics and pharmacodynamics of oral etoposide.Br J Clin Pharmacol.2001; 52: 511–519.
73.
MillerA.A., RosnerG.L., RatainM.J.. Pharmacology of 21-day oral etoposide given in combination with i.v. cisplatin in patients with extensive-stage small cell lung cancer: a Cancer and Leukemia Group B study (CALGB 9062).Clin Cancer Res.1997; 3: 719–725.
74.
AndoM., MinamiH., AndoY.. Pharmacological analysis of etoposide in elderly patients with lung cancer.Clin Cancer Res.1999; 5: 1690–1695.
75.
AitaP., RobieuxI., SorioR.. Pharmacokinetics of oral etoposide in patients with hepatocellular carcinoma.Cancer Chemother Pharmacol.1999; 43: 287–294.
76.
KawashiroT., YamashitaK., ZhaoX.J.. A study on the metabolism of etoposide and possible interactions with antitumor or supporting agents by human liver microsomes.J Pharmacol Exp Ther.1998; 286: 1294–1300.
77.
DeesE.C., O'ReillyS., GoodmanS.N.. A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer.Cancer Invest.2000; 18: 521–529.
78.
LiJ., GwiltP.R.. The effect of age on the early disposition of doxorubicin.Cancer Chemother Pharmacol.2003; 51: 395–402. Epub 2003 Apr 1.
79.
SwainS.M., WhaleyF.S., EwerM.S.. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.Cancer.2003; 97: 2869–2879.
80.
LichtmanS.M.. Physiological aspects of aging. Implications for the treatment of cancer.Drugs Aging.1995; 7: 212–225.
81.
DaugaardG., AbildgaardU.. Cisplatin nephrotoxicity. A review.Cancer Chemother Pharmacol.1989; 25: 1–9.
82.
CubilloA., CornideM., LopezJ.L.. Renal tolerance to cisplatin in patients 70 years and older.Am J Clin Oncol.2001; 24: 192–197.
83.
LangerC.J., ManolaJ., BernardoP.. Cisplatin-based therapy for elderly patients with advanced nonsmall-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial.J Natl Cancer Inst.2002; 94: 173–181.
84.
CalvertA.H., EgorinM.J.. Carboplatin dosing formulae: gender bias and the use of creatinine-based methodologies.Eur J Cancer.2002; 38: 11–16.
85.
EgorinM.J., Van EchoD.A., OlmanE.A.. Prospective validation of a pharmacologically based dosing scheme for the cis-diamminedichloroplat-inum(II) analogue diamminecyclobutanedicarboxylatoplatinum.Cancer Res.1985; 45(12 Pt 1): 6502–6506.
86.
CalvertA.H., NewellD.R., GumbrellL.A.. Carboplatin dosage: prospective evaluation of a simple formula based on renal function.J Clin Oncol.1989; 7: 1748–1756.
87.
ChatelutE., CanalP., BrunnerV.. Prediction of carboplatin clearance from standard morphological and biological patient characteristics.J Natl Cancer Inst.1995; 87: 573–580.
88.
GrahamM., LockwoodG., CunninghamD.. Pharmacokinetics of oxaliplatin in special patient populations.Proc Annu Meet Am Soc Clin Oncol.1999: 728. Abstract.
89.
TakimotoC.H., RemickS.C., SharmaS.. Administration of oxaliplatin to patients with renal dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group.Semin Oncol.2003; 30(4 suppl 15): 20–25.
90.
GrahamM.A., LockwoodG.F., GreensladeD.. Clinical pharmacokinetics of oxaliplatin: a critical review.Clin Cancer Res.2000; 6: 1205–1218.
91.
DoroshowJ.H., SynoldT.W., GandaraD.. Pharmacology of oxaliplatin in solid tumor patients with hepatic dysfunction: a preliminary report of the National Cancer Institute Organ Dysfunction Working Group.Semin Oncol.2003; 30(4 suppl 15): 14–19.
92.
GoldbergR.M., Tabah-FischI., BleibergH.. Pooled analysis of safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly in elderly patients with colorectal cancer.J Clin Oncol.2006; 24: 4085–4091.
93.
BealeP., JudsonI., MooreS.. Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide.Cancer Chemother Pharmacol.1999; 44: 389–394.
94.
JenJ.F., CutlerD.L., PaiS.M.. Population pharmacokinetics of temozolomide in cancer patients.Pharm Res.2000; 17: 1284–1289.
95.
BorkowskiJ.M., DuerrM., DonehowerR.C.. Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data.Cancer Chemother Pharmacol.1994; 33: 493–496.
96.
ExtermannM., AaproM., BernabeiR.. Use of comprehensive geriatric assessment in older cancer patients: recommendations from the task force on CGA of the International Society of Geriatric Oncology (SIOG).Crit Rev Oncol Hematol.2005; 55: 241–252.
97.
HurriaA., GuptaS., ZaudererM.. Developing a cancer-specific geriatric assessment: a feasibility study.Cancer.2005; 104: 1998–2005.
