It's Time for Action on Shortage of Elderly in Clinical Trials

Maurie Markman, MD

It has long been recognized that the elderly, an age bracket variously defined in the medical literature, are acutely underrepresented in the clinical trials that help to define the standards of care in oncologic management in the United States.¹

A recent report about the representation of these patients in breast cancer studies demonstrates just how little has changed over the years.2 An examination of accrual into breast cancer trials conducted by the Alliance for Clinical Trials in Oncology, a National Cancer Institute (NCI)-sponsored cooperative group, from 1985 to 2012 revealed that 17% of the participants overall were aged ≥65 years, and less than 15% were ≥70 years. To put this dismal record in perspective, it is important to know that nearly one-half (47%) of all breast cancer deaths in the United States each year are estimated to occur in women ≥70 years of age.²

Prevalence of Comorbidities

Further, the percentage of the elderly within the US population is growing at a rapid pace. The percentage of individuals ≥65 years is estimated to increase from 12% in 2004 to 20% in 2030.³ Additionally, once an individual attains the status of being ≥65 years, she or he can anticipate living longer than in the past. For example, the life expectancy after reaching the age of 65 was 13.8 years in 1950; this increased to 18.7 years in 2004.³When discussing the participation of elderly patients in cancer clinical trials, we must clearly recognize that this lack of representation cannot be viewed merely as an academic or bureaucratic exercise where the intent is simply to be certain that there is a numerical match for the various populations of individuals seen in an oncologist’s clinical practice.

Although individuals ≥65 years make up the majority of patients seen in the real world of cancer practice, it is far more important to emphasize that, as a group, they possess highly clinically relevant features that may be quite different from the younger patient population found in most clinical trials. These features may substantially alter the benefit-to-risk ratio associated with a given antineoplastic therapy or modify the manner in which a particular strategy should be delivered (eg, dose, schedule).

For example, in a recently reported survey of residents (n = 138,858) of Olmsted County, Minnesota, the percentage of individuals who had more than 1 of 20 common chronic conditions (eg, hypertension, diabetes, coronary artery disease, osteoporosis, congestive heart failure, dementia) increased with patient age.⁴ Overall, 22.6% of the entire population had ≥2 of these conditions but, this percentage was 77.3% among individuals 65 years of age For members of this population aged ≥80 years, nearly 88% of men and 86.4% of women had ≥2 of these chronic illnesses.

Real-World Clinical Impact

Perhaps even more striking was the observation that, of the individuals ≥65 years, 26.8% of women and 30.7% of men were known to have ≥5 chronic conditions; these percentages rose to 50.5% and 41.1%, respectively, among those ≥80 years. One can only imagine the potential for adverse events associated with cancer treatments (eg, surgery, chemotherapy, immunotherapy) in the presence of 1 or more of these common comorbidities or the medications employed in their management.These concerns are far more than theoretical. Consider, for example, hypertension, a potentially serious adverse event associated with antiangiogenic agents widely employed in many settings in the management of advanced malignancies. A national survey reported that 64% and 77% of older men and women, respectively, were either taking medications for high blood pressure or at least had a measured elevated blood pressure.³ In addition, according to data from 2001 to 2004, as many as a quarter of the elderly had a diagnosis of diabetes and obesity (body mass index ≥30), an increasingly recognized risk factor for inferior cancer-related survival, was reported in 26% of older men and 31% of older women.³

As concerning as these facts may be regarding the potential lack of relevance of existing clinical trial data to inform optimal treatment of cancer in elderly patients in a given clinical setting, real world experience is even more alarming. The results of a recent report involving 250 patients ≥65 years (mean age 73) treated at 1 of 8 well-recognized cancer programs revealed that 58% experienced grade ≥3 toxicity.⁵ It is reasonable to speculate that the therapeutic regimens selected, including their doses and schedules, were based on published data from clinical trials that suggested an acceptable risk-benefit profile for the program. Unfortunately, the data—including information the FDA employs to define on-label drug usage—may have been irrelevant in a real-world clinical setting.

Although there has been much rhetoric over the years about the need to come up with a way to substantially increase accrual of elderly patients into clinical trials, the results of these efforts have clearly been unacceptable and, in fact, nothing short of dismal. It is time for society to strongly suggest—even demand—that study sponsors, such as the NCI, the National Institutes of Health, pharmaceutical companies, and private foundations, and regulatory bodies become far more proactive in this area by encouraging or mandating that clinical research programs find appropriate strategies to specifically include the rapidly growing population of elderly patients with cancer.

References

1. Lewis JH, Kilgore ML, Goldman DP, et al. Participation of patients 65 years or older in cancer clinical trials. J Clin Oncol. 2003;21(7):1383- 1389. doi: 10.1200/JCO.2003.08.010.
2. Freedman RA, Foster JC, Seisler DK, et al. Accrual of older patients with breast cancer to Alliance Systemic Therapy Trials over time: protocol A151527. J Clin Oncol. 2017;35(4):421-431. doi: 10.1200/ JCO.2016.69.4182.
3. Kramarow E, Lubitz J, Lentzner H, Gorina Y. Trends in the health of older Americans, 1970-2005. Health Aff (Millwood). 2007;26(5):1417- 1425. doi: 10.1377/hlthaff.26.5.1417.
4. Rocca WA, Boyd CM, Grossardt BR, et al, Prevalence of multimorbidity in a geographically defined American population: patterns by age, sex, and race/ethnicity. Mayo Clin Proc. 2014;89(10):1336-1349. doi: 10.1016/j.mayocp.2014.07.010.
5. Hurria A, Mohile S, Gajra A, et al. Validation of a prediction tool for chemotherapy toxicity in older adults with cancer. J Clin Oncol. 2016;34(20):2366-2371. doi: 10.1200/JCO.2015.65.4327.