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Journal of Clinical Oncology, Vol 22, No 22 (November 15), 2004: pp. 4626-4631 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.02.175
Enrollment of Elderly Patients in Clinical Trials for Cancer Drug Registration: A 7-Year Experience by the US Food and Drug AdministrationFrom the Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, MD Address reprint requests to Lilia Talarico, MD, Division of Oncology Drug Products, HFD 150, Food and Drug Administration, 1451 Rockville Pike, Rockville, MD 20857; e-mail: Talarico{at}cder.fda.gov
PURPOSE: To analyze the age-related enrollment of cancer patients onto registration trials of new drugs or new indications approved by the US Food and Drug Administration from 1995 to 2002.
PATIENTS AND METHODS: This study involved retrospective analyses of demographic data of cancer patients enrolled onto registration trials. The data on 28,766 cancer patients from 55 registration trials were analyzed according to age distributions of
RESULTS: The proportions of the overall patient populations aged CONCLUSION: Elderly were under-represented in the registration trials of new cancer therapies. Various strategies may be needed to evaluate cancer therapies for the elderly in prospective clinical trials and to improve cancer care in the elderly population.
Approximately 60% of all new cases of cancer and 70% of all cancer-related deaths occur in the elderly population, defined as comprising individuals aged  65 years.1 Increasing life expectancy of the western industrialized population and increasing cancer incidence with aging will result in expansion of the elderly cancer population. During the next three decades, the elderly will represent 20% of the US population and the absolute cancer number in the elderly will double.1 Despite being at greatest risk of cancer, elderly are often under-represented in clinical trials of new cancer treatments2-5 and are less likely to receive definitive or adequate cancer therapy.6,7
A study conducted by the Southwest Oncology Group (SWOG) analyzed the data on 16,396 consecutive patients with 15 cancers of advanced stage enrolled onto 164 active clinical trials from 1993 to 1996.3 The study disclosed that patients aged
A subsequent study analyzed 59,300 patients enrolled onto 495 clinical trials of 18 cancers sponsored by the National Cancer Institute (NCI) and carried out by cooperative oncology groups from 1997 to 2000.4 The enrollment of elderly patients was evaluated across trials and for trials stratified by phase, cancer type, and cancer stage. In this study, the overall proportion of patients aged
A study conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) analyzed data from 4,174 patients enrolled onto 69 trials of 14 cancer types from 1993 to 1996.5 The study included phase I, II, and III clinical trials of adjuvant and metastatic disease treatments. Patients aged The objective of our study was to evaluate the impact of age on patient enrollment in clinical trials for registration of new cancer drugs or new cancer indications approved by the US Food and Drug Administration (FDA) from 1995 to 2002. The proportions of elderly patients in the registration trials were compared with the estimated proportions of elderly in the US population with the corresponding cancer type and stage.
Registration Trial Study Population Data from all patients enrolled onto the registration trials of new cancer drugs or new indications of marketed cancer drugs approved by the FDA from 1995 to 2002 for the treatment of leukemia, lymphoma, and cancers of the breast, lung, colon or rectum, ovary, pancreas, and CNS were analyzed for age distribution. For each cancer, the percentages of study patients aged 65, 70, and 75 years were compared with the corresponding percentages in the US cancer population. Breast cancer trials that enrolled only premenopausal patients or assessed cancer prevention in high-risk populations were not included. The study did not include hormonal therapy of prostate cancer, radiopharmaceuticals, and biologic oncology products that were reviewed by other divisions of the Center for Drugs Evaluation and Research or by the Center for Biologic Evaluation and Research of the FDA. Given that our study focused on the clinical trials for registration of new cancer regimens for different cancer types and stages, the accrual rates of elderly were analyzed for drug class, disease stage, and treatment indication. Breast cancer trials included hormonal and chemotherapy trials for the treatment of early and advanced disease. The clinical trials of lung, colon or rectum, pancreas, ovary, and CNS cancers evaluated only chemotherapy regimens for first- or second-line therapy of advanced or metastatic, or refractory disease. Leukemia and lymphoma clinical trials included cytolytic and noncytolytic drug regimens for the treatment of chronic myelogenous leukemia in chronic phase, in blastic phase, and in accelerated phase; acute promyelocytic leukemia; acute myelogenous leukemia; and cutaneous T-cell lymphoma.
Surveillance, Epidemiology, and End Results Program and US Cancer Population
Comparison of Registration Trials and US Cancer Population
A total of 28,766 patients were enrolled onto 55 registration trials involving the following cancers: breast (n = 14), lung (n = 11), colorectal (n = 7), pancreas (n = 2), CNS (n = 1), ovary (n = 7), leukemia (n = 11), and cutaneous T-cell lymphoma (n = 2). Overall, elderly patients aged 65 years comprised 36% of the total study population as compared with 60% in the US cancer population (P < .001). The discrepancy between incidence and representation increased progressively with increasing age. The overall enrollments of patients 70 and 75 years of age were 20% and 9% compared with 46% and 31%, respectively, in the US cancer population (P value for trend < .05). The data are shown in Figure 1.
The proportions of patients 65 years of age in the registration trials for each cancer compared with the proportions of elderly in the US population with the corresponding cancers and in the corresponding age groups are shown in Figure 2. The percentage of elderly patients enrolled onto the registration trials was significantly lower than the corresponding rates in the US general cancer population for each cancer type (P < .001), except for breast cancer trials of hormonal therapies. The proportions of elderly patients with breast cancer enrolled onto the registration trials of hormonal therapy for adjuvant or advanced disease were 45% and 50%, respectively, as compared with 48% in the US breast cancer population. In contrast, the proportions of elderly patients enrolled onto the chemotherapy trials for adjuvant and advanced disease were 6% and 15%, respectively, as compared with 48% in the US breast cancer population. Patients in the age group 65 to 69 years accounted for only 4% of breast cancer patients entered onto adjuvant chemotherapy trials and only 9% of patients entered onto chemotherapy trials for advanced/metastatic disease. Excluding all trials of hormonal therapy for breast cancer, the overall enrollment of patients aged 65, 70, and 75 years decreased to 25%, 12%, and 4%, as compared with 60%, 46%, and 31%, respectively, for the corresponding age group in the US cancer population.
Patients 70 years or older accounted for most of the under-representation; however, decreased enrollment of patients in the age group of 65 to 69 years was noted in the clinical trials of breast cancer adjuvant and advanced disease chemotherapy, therapy for CNS cancer, first-line therapy of ovarian cancer, and therapy of leukemia. No significant imbalance was noted in the enrollment rates of elderly by sex (where applicable) or ethnicity compared with the overall populations enrolled onto each study.
Our study is the first report on the enrollment of elderly in registration trials of cancer treatment. The study reflects the participation of elderly cancer patients in the clinical trials of currently available regimens for specific cancer indications. We found that the overall proportion of patients 65 years enrolled onto the trials was 36% compared with 60% in the overall US population with cancer, and that the discrepancy between cancer incidence and study enrollment increased with age. Patients aged 70 years accounted for most of the under-representation; however, discrepancy between incidence and participation of patients in the age group 65 to 69 years was observed in clinical trials of leukemia, CNS, brain, ovary, and breast (chemotherapy) cancers. Although participation in clinical trials decreased in the population aged 70 years, the cancer incidence increases in this age group for most cancers in the study.
The overall enrollment of elderly patients
Although cancer is a leading cause of death in the US elderly population, the participation of adult and elderly cancer patients in clinical trials is age dependent and limited. Only 1.5% of patients Since 1983, the FDA has proposed (and most recently insisted on) the evaluation of drugs in demographic (age, sex, race) and disease (concomitant morbidities or medications) subsets of the total population.12 The program began with the development of the Guideline for the Study of Drugs Likely to Be Used in the Elderly. The Guideline, proposed in 198313 and issued in 1989,14 recommended that elderly patients not be excluded from clinical trials so that potential differences in treatment effects between younger and older populations could be detected. The Guideline did not recommend separate studies in elderly, nor did it specify a particular desirable fraction of overall exposure that should be achieved by patients. Because the elderly are more likely to have reduced organ function, and concomitant morbidities or medications, the Guideline also addressed the need for pharmacokinetic screens to identify relevant age-related differences between the elderly and general population.14 The medical literature has documented that elderly cancer patients continue to be under-represented in new cancer treatment clinical trials.2-5,15 Elderly patients also receive standard chemotherapy less often than do younger patients.6,16-18 Age-associated decline in functional reserve, increase in comorbid conditions, concomitant medication usage, and delayed diagnosis all limit the accrual of the elderly in clinical trials and aggressive therapeutic interventions.19,20 Nonclinical factors are also operative in limiting trial participation: older patients are less well informed about clinical trials and new therapies, and are less likely to participate in therapeutic decision making. Concerns regarding health care cost, lack of social and home care support, difficulties with access to clinics and hospitals, or availability of cancer centers constitute significant socioeconomic barriers, not usually considered in the evaluation and treatment of younger patients.20-24 Although age per se is not always a predictor of poor outcome, advancing age is a heterogeneous and individual process associated with increasing health problems,19,20 and with disease characteristics that may negatively alter the risk and benefit outcome of cancer therapy.25,26 A limited number of studies have provided information on the tolerability and benefits of chemotherapy in the elderly.27-29 However, there is evidence that inadequate treatment may result in inferior outcomes.30 Physicians may be reluctant to recommend investigational or standard cancer chemotherapy for older patients because of real or perceived notions that the potential gains in overall survival do not outweigh the morbidity and poor quality of life associated with cancer therapy. A physician's decision regarding aggressive therapy in elderly cancer patients can also be influenced by the patient's chronological age more than by the patient's biologic or functional age and projected life expectancy.31-33 A survey of US oncologists indicated that 51% excluded patients from clinical trials on the basis of age alone.33 At the same time, elderly cancer patients may be unwilling to participate in clinical trials on preconceived notions of treatment toxicity and unfavorable risk-benefit outcome. However, the acceptance of chemotherapy by the elderly has not been studied extensively. Our retrospective study does not provide information to determine the proportion of elderly cancer patients not enrolled onto clinical trials because of physician's judgment, patient's preference, or eligibility requirements. In a case-control study, 34% of patients with stage II breast cancer who were eligible for a treatment trial were offered participation and enrolled onto clinical trials, compared with 68% of younger patients.34 Elderly patients had more comorbidities; however, when controlling for performance status and comorbidity, age and disease stage remained highly significant in predicting whether a patient was offered a clinical trial. The primary reason for not offering a trial was concern for treatment toxicity for the older patients and unawareness of trial availability for younger patients. Of the patients offered a trial, participation was similar for older and younger patients, 50% and 56% respectively, indicating that physicians' judgment rather than patients' decision determined study participation. A subsequent survey assessed the oncologists' perception of the barriers to accrual and the interventions required to improve accrual.35 The most important barriers reported included presence of comorbidities that, although not necessarily excluded by protocol, were believed to affect the treatment response; patients' low level of understanding and compliance with complex protocols; inability to meet eligibility criteria; and treatment toxicity. Effective interventions proposed in the survey included educational material to physicians regarding treatment toxicities and the need for simpler protocols and less toxic therapy. In our study, the participation of elderly women with breast cancer in the registration trials of hormonal therapy for both early and advanced disease was consistent with the age distribution of the disease in the general breast cancer population. Hormonal therapy has been shown to be well tolerated and effective in reducing the recurrence and death risks in women of all ages with hormone receptor-positive breast cancer. The registration trials reflected the general acceptance of hormonal therapy in clinical practice and its perceived tolerability in older patients. In contrast, the use of chemotherapy in the adjuvant setting for older women is less accepted. The benefits of adjuvant chemotherapy decrease as age and comorbidities increase and as life expectancy decreases. Adjuvant chemotherapy is recommended primarily for high-risk patients with positive lymph nodes and hormone receptor-negative tumors.36 Its use is based on the patient's health status and its impact on life expectancy. The registration trial of adjuvant chemotherapy for high-risk patients, all with positive lymph nodes and 40% hormone receptor-negative disease, included only 6% elderly patients. As reported in the NCI and NCIC-CTG trials,4,5 more elderly breast cancer patients were enrolled onto chemotherapy registration trials of advanced/metastatic disease than in adjuvant chemotherapy trials (15% and 6%, respectively; P < .01). No consistent pattern of under-representation was noted in the cancer registration trials for first- or second-line treatment of advanced or refractory disease.
An essential requirement of clinical trials is the enrollment of patients in sufficient number and with appropriate characteristics to allow analysis and generalization of the results to the intended population. Arbitrary restrictions based on chronological age are no longer applied to clinical trials; therefore, elderly patients, including those in the older age range ( The need to develop and evaluate cancer treatments in the elderly will increase as this population continues to expand with time. Progress in the understanding of cancer biology has introduced numerous cancer therapies aimed at selective modifications of cellular and molecular oncogenic mechanisms. These new and novel targeted agents are perceived as less toxic and better tolerated than traditional chemotherapy. Clinical trials with larger accrual of cancer patients, and elderly patients in particular, will be critical for the assessment of the efficacy and safety of these new treatments and to detect and identify disease- or patient-related factors that may influence the response to therapy.
The authors indicated no potential conflicts of interest.
We thank Milton Eisner, PhD, National Cancer Institute, for providing the SEER-11 data for the cancer populations and for his valuable assistance with the analyses of the SEER Program Data.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL. The views expressed are the result of independent work and do not represent the viewpoints or findings of the US Food and Drug Administration. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to evaluate the proportions of elderly patients enrolled onto registration trials as compared with the proportions of elderly in the US cancer population for each cancer type, age group, and treatment indication. A two-sided P value of less than .05 was used in the analyses. 
