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Journal of Clinical Oncology, Vol 25, No 34 (December 1), 2007: pp. 5350-5351 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.7125
Incorporation of Geriatric Principles in Oncology Clinical TrialsCity of Hope, Duarte, CA Sixty percent of cancer incidence and 70% of cancer mortality occur in adults greater than 65 years old. With colon cancer in particular, the median age at diagnosis is 73 years.1 The major challenge in caring for older adults with cancer rests with the lack of data from prospective clinical trials. Evidence-based oncology guidelines are primarily based on clinical trials in which older adults are either absent or underrepresented and trial participants are typically younger than the majority of patients who contract the disease.2-4 The data are especially sparse for individuals age 75 and older. This problem is becoming increasingly critical in light of the rapid growth of the aging population, with the number of adults age 65 and older in the United States projected to double between now and 2030.5 This problem in need of redress may slowly be turning around. In this issue, Hochster et al6 report their study of the efficacy and tolerance of cancer therapy in older adults. The authors are to be congratulated for performing this study in a population with a mean age of 81 years and with a sizeable proportion of the study population falling in what is considered the oldest-old age group of 85 to 90 years. Their phase II study of tegafur-uracil (UFT) with leucovorin was conducted in patients with metastatic colon cancer. The authors report a response rate to UFT and leucovorin of 22% and a median overall survival time of 13 months; however, this efficacy comes at the cost of a 55% rate of grade 3 to 4 toxicity, most commonly GI, with 45% of patients requiring dose modification. Accrual was relatively expeditious over a 1-year period; however, reporting of the data took considerably longer, and several newer therapies and approaches to the treatment of metastatic colon cancer have evolved in the meantime. Although UFT was not a drug approved by the US Food and Drug Administration, this study by Hochster et al6 provides us with the opportunity to identify and discuss ways of optimizing clinical trial design in older adults with cancer. Phase II studies of cancer therapies in older adults are essential because age-related changes in physiology can affect the pharmacokinetics and pharmacodynamics of cancer therapy. With increasing age, renal function declines, and renal blood flow and glomerular filtration rate decrease.7 The decline in renal function may not be apparent when measuring serum creatinine alone because of a decrease in muscle mass with age.8 In addition, autopsy studies show a decrease in the liver hepatic enzyme content in older adults.9 Age-related changes in splanchnic blood flow, gastric motility, digestive enzymes, and mucosal atrophy can affect the bioavailability of oral cancer therapy.10-12 Older adults are more vulnerable to mucositis and the GI side effects of cancer therapy, making early management of diarrhea and fluid resuscitation critical. Bone marrow reserve also diminishes with age, placing older adults at risk for myelosuppressive complications.13,14 Understanding the pharmacokinetics and pharmacodynamics of cancer therapy in older adults can lead to future interventions that minimize the risk and maximize treatment efficacy. Although phase II studies of cancer therapies in older adults are desperately needed, the usual study end points of efficacy and toxicity do not fully address the risks and benefits of therapy for an older adult. In the study by Hochster et al,6 for example, several additional questions come to mind. Who were the older adults included in this study: how active were they, what were their other medical problems, did they have cognitive problems, and did they have social support? What baseline characteristics other than age placed an older adult at risk for toxicity? What was the short- and long-term impact of therapy on the patients’ ability to live independently? Incorporation of geriatric principles in oncology clinical trials could have helped to answer these questions. It is generally recognized that chronologic age tells relatively little about an older adult's physiologic age. Oncologists allude to this when they describe an older adult as a "young" 80-year-old patient or an "old" 80-year-old patient, implying factors other than age that describe the physiologic state. Geriatricians address this by routinely performing a geriatric assessment, which measures independent predictors of morbidity and mortality in older adults. This assessment evaluates functional status, comorbid medical conditions and concomitant medications, cognitive function, psychological state, and social support. Incorporation of a geriatric assessment in oncology clinical trials could capture the baseline characteristics particular to the older adults enrolled onto the trial, assess for competing causes of morbidity and mortality, and potentially identify factors other than chronologic age that predict which older adults are most likely to develop a grade 3 or 4 toxicity or require a dose modification. Follow-up geriatric assessments at scheduled time points after initiation of the cancer therapy can quantify the longitudinal impact of the therapy on the older adult's functional status and other geriatric assessment parameters. Little is known regarding the trade-off an older adult with cancer would be willing to endure for a noncurative therapy that carries a 22% response rate and a 55% risk of grade 3 or 4 toxicity. However, a study by Fried et al15 regarding the treatment preferences in older adults provides insight into the key elements influencing an older adult's decision-making process. In this study, the majority of older adults stated that they would forgo a life-saving therapy that could lead to severe functional and cognitive impairment. Therefore, the decisions regarding cancer therapy can only be made in an informed manner if we understand the longitudinal impact of cancer and cancer therapy on the quality of remaining survival and understand the characteristics that place certain older adults at risk for complications. These data, placed in the context of the treatment's efficacy, can ultimately allow the patient and the doctor to weigh the risks and benefits of therapy and provide a platform for future research to develop and test interventions to improve treatment tolerance. The intersection between cancer and aging provides a unique opportunity for collaboration between geriatrics and oncology and the chance to transform cancer care for older adults into evidence-based state-of-the-art treatment. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS A.H. is supported by K23 AG026749-01 Paul Beeson Career Development Award in Aging Research and American Society of Clinical Oncology–Association of Specialty Professors–Junior Development Award in Geriatric Oncology. REFERENCES 1. Ries LAG, Harkins D, Krapcho M, et al: SEER cancer statistics review, 1975-2003. http://seer.cancer.gov/csr/1975_2003/ 2. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer- treatment trials. N Engl J Med 341:2061-2067, 1999 3. Yee KW, Pater JL, Pho L, et al: Enrollment of older patients in cancer treatment trials in Canada: Why is age a barrier? J Clin Oncol 21:1618-1623, 2003 4. Trimble EL, Carter CL, Cain D, et al: Representation of older patients in cancer treatment trials. Cancer 74:2208-2214, 1994[CrossRef][Medline] 5. He W, Sengupta M, Velkoff V, et al: U.S. Census Bureau, Current Population Reports, P23-209, 65+ in the United States: 2005. Washington, DC, US Government Printing Office, 2005 6. Hochster HS, Luo W, Popa EC, et al: Phase II study of uracil-tegafur with leucovorin in elderly ( 7. Lindeman RD, Tobin J, Shock NW: Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc 33:278-285, 1985[Medline] 8. Fehrman-Ekholm I, Skeppholm L: 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 38:73-77, 2004[CrossRef][Medline] 9. Sotaniemi EA, Arranto AJ, Pelkonen O, et al: Age and cytochrome P450-linked drug metabolism in humans: An analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 61:331-339, 1997[CrossRef][Medline] 10. Lee M: Age-related changes in gastric blood flow in rats. Gerontology 42:289-293, 1996[Medline] 11. Goldschmiedt M, Barnett CC, Schwarz BE, et al: Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women. Gastroenterology 101:977-990, 1991[Medline] 12. Guslandi M, Pellegrini A, Sorghi M: Gastric mucosal defenses in the elderly. Gerontology 45:206-208, 1999[CrossRef][Medline] 13. ten Tije AJ, Verweij J, Carducci MA, et al: Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the elderly. J Clin Oncol 23:1070-1077, 2005 14. Dees EC, O'Reilly S, Goodman SN, et al: A prospective pharmacologic evaluation of age-related toxicity of adjuvant chemotherapy in women with breast cancer. Cancer Invest 18:521-529, 2000[Medline] 15. Fried TR, Bradley EH, Towle VR, et al: Understanding the treatment preferences of seriously ill patients. N Engl J Med 346:1061-1066, 2002
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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75 years old) patients with colorectal cancer: ECOG 1299. J Clin Oncol 25:5397-5402, 2007
