In a Disease of Aging, Patients in Trials Get Younger and Younger

Cancer is a disease of aging, but the median age of participants in clinical trials of oncologic treatments keeps getting younger, according to a new analysis.

The age disparities between cancer patients in clinical trials and their real-world counterparts with the same tumor types are "pervasive and worsening," say the study authors, led by Ethan Ludmir, MD, University of Texas MD Anderson Cancer Center in Houston.

The findings come from a meta-analysis of 302 clinical trials with 262,354 participants enrolled between 1994 and 2015.

The median age of these participants was 6.49 years younger (P < .001) than the median age of real-world patients with the same cancers in a federal database. That's a "substantial difference," the authors comment.

Further, the investigators' analysis also revealed an apparent "widening gap" between trial patients' and real-world patients' median ages over time — at a rate of −0.19 years annually (P = .04).

In short, clinical trial patients are getting younger and younger compared with real-world patients.

Younger patients are desirable because, as a group, they can better tolerate toxicities and adverse events than older patients, which could determine a trial's success or failure.

The study was published online June 3 in JAMA Oncology.

However, clinicians should not be deterred by any of this, said Ludmir in an email to Medscape Medical News. "The message we'd like to give fellow oncologists: don't let age alone be the reason a patient is not offered an opportunity to participate in a clinical trial," he commented.

Ludmir also emphasized that cancer patients, as a demographic, are getting older and should be assessed by their functionality and other factors for trial participation. "By 2030, 70% of all new cancer diagnoses will be among patients aged 65 and over," he said.

The study authors point out that older cancer patients have long been underrepresented in clinical trials, a fact first established 15-20 years ago in an analysis of National Cancer Institute (NCI) funded trials.

The investigators wondered: has this age problem persisted in more modern settings, including for new targeted therapies and among industry-sponsored trials?

And so they looked at clinical trials of treatments for the four most common cancers (breast, prostate, colorectal, and lung) and compared the median age of participants versus the median age of same-tumor patients at diagnosis in the NCI Surveillance, Epidemiology and End Results (SEER) database.

In other words, they compared the median ages of cancer patients from the universe of randomized clinical trials (RCTs) with those of the real-world population. The RCTs included systemic drugs (n = 247), radiation (n = 7), surgery (n = 2), and supportive care (n = 45).

"We hope this paper encourages self-reflection and conscientious attention to age inclusion for clinical trials," said senior author C. David Fuller, MD, also from MD Anderson.

"Older adults with cancer continue to be vastly underrepresented in cancer clinical trial participation," summarized Beverly Moy, MD, MPH, Massachusetts General Hospital (MGH) Cancer Center, Boston, who was asked for comment.

It would be clarifying if trialists called out this shortcoming, said Bishal Gyawali, MD, PhD, Queens University, Kingston, Ontario, Canada, who was also invited to comment.

I don't remember ever seeing a trial publication that has discussed the age of trial participants as a limitation. Bishal Gyawali, MD, PhD

"I don't remember ever seeing a trial publication that has discussed the age of trial participants as a limitation," he said. "No trial has ever mentioned that 'the participants in our trial were younger and fitter than the routine patients with this cancer and thus may not be representative of real-world outcomes.'"

Medscape Medical News passed along Gyawali's quote to MD Anderson's Fuller, who responded: "I agree with the comment!"

Trialists may ignore this question of the applicability of their RCT results, but other oncologists are taking notice, suggested Gyawali.

"That RCTs include fitter patients, exclude elderly patients, and thus are not representative of real-world patients, is an acknowledged problem in oncology. For this reason, ASCO has also recently issued a guideline recommending wider inclusion of elderly patients in cancer RCTs," he said.

MGH's Moy echoed some of these comments: "There has been a movement from the entire oncology community, especially the geriatric oncology community, to call attention to this issue [of underrepresentation of older patients]."

The study authors suggest it may be time to add age to the list of disparities such as sex, race/ethnicity, and socioeconomics that commonly limit the findings of clinical trials in oncology.

Nonetheless, Moy reminded that there are various "barriers" to enrolling older cancer patients in trials, including financial barriers that arise out of problems with insurance in the United States, particularly Medicare.

A Novel Finding

The investigators report that the majority of the trials (n = 247, 82.5%) in their review were industry-funded. About three quarters of the trials were multinational.

The investigators found that age disparities were greater among industry-funded trials compared with nonindustry-funded trials (mean difference in median age, −6.84 vs −4.72 years; P = .002).

This is a novel finding, say the authors. "No prior studies have demonstrated demographic disparities among [cancer clinical] trial participants as a function of industry funding," they write.

Notably, most of the clinical trials (n = 276) did not have enrollment criteria that restricted access based on age. Only 26 trials had such age restrictions.

However, the investigators report that enrollment criteria restrictions — based on performance status or age cutoffs — were associated with age disparities. Nonetheless, industry-funded trials were "not more likely to use these enrollment restrictions than nonindustry-funded trials," observe the authors.

Age disparities were also larger among trials that evaluated a targeted systemic therapy (ie, monoclonal antibody or small molecule inhibitor) compared with those that tested cytotoxic chemotherapy (−7.72 vs −5.30 years; P = .01).

In the current study, the investigators cannot identify exactly how clinical trial participants ended up being much younger than real-world cancer patients, but the authors believe it is an important matter to address.

"With an increasing role of industry funding among cancer trials, efforts to understand and address age disparities are necessary to ensure generalizability of trial results as well as equity in trial access," they conclude.

Disclosures for the authors are listed in the article. Gwayali and Moy have reported no relevant financial relationships.

JAMA Oncol. Published online June 3, 2019. Abstract

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