A gaping hole in cancer treatment trials

This article was originally published underdark magazine.

In October 2021, 84-year-old Jim Yerdel was diagnosed with stage 3 lung cancer. The first drug he tried disrupted balance and coordination, Yedel recalls, so his doctor cut the dosage in half to minimize side effects. Additionally, his doctor recommended a course of treatment that included chemotherapy, radiation, and drugs that target specific genetic mutations. The combination is highly effective, at least for young people, but it can also be “incredibly toxic” for older and frail people, says Yedel’s daughter, a palliative care expert at Baylor College of Medicine. One Elizabeth Coubert says: law.

Clinical trials of new cancer treatments, including the treatment proposed by Yedel, often underestimate the proportion of older patients. As a result, he learned of the potential toxicity only when his daughter-in-law witnessed serious side effects of the treatment on the elderly in the clinic.

This lack of age-specific data has significant implications for clinical care, as older people are more likely to be diagnosed with cancer than younger people.In the United States, approximately 42 percent The proportion of people with cancer who are over 70 years of age, and that number is likely to increase in the next few years, is less than a quarter participating in clinical trials. new cancer treatments. Many of the participants will be the healthiest seniors and may not have common age-related conditions such as diabetes or declining kidney or heart function, says a medical oncologist and National Cancer Institute researcher.・Mina Sedrak, Deputy Director of the Center for Aging, said: City of Hope National Medical Center.

For decades, clinical trials have tended to exclude older participants because of preexisting conditions, concerns about other drugs, and participants’ ability to travel to the trial site. As a result, clinicians cannot be sure that approved anticancer drugs will work as expected in clinical trials in people most likely to develop cancer. This lack of data means that older cancer patients must decide whether to choose treatments that are less effective and may cause more side effects in clinical trials than younger patients. are doing.

This evidence gap spans the entire spectrum of cancer treatment, from chemotherapy and radiation to immune checkpoint inhibitors, with sometimes disastrous consequences. For example, many chemotherapy treatments have proven to be highly toxic in the elderly, a finding that only became apparent after drugs were approved for use in the elderly. “This is a big problem,” said Sedlak. To minimize side effects, doctors often Fine tune dosage Such as the duration of medications given to the elderly, but these doctors do this without real guidance.

Despite the recommendation from Funder and Regulatory authorityeven as Extensive media coverage, has not changed much in the last 30 years. “We’re in this field where everyone agrees that this is a problem, but there’s little guidance on how to improve for older people,” says Kubale. . “The impact in the real world is huge.”

Post-approval studies of cancer drugs have helped clarify the gap between how these drugs are used in clinical trials and in clinics across the country. ing.

Read: America’s most popular drug has mysterious side effects. I finally understand why.

For example, when Yale University physician and cancer researcher Carrie Gross set out to study the use of a new class of cancer drugs known as immune checkpoint inhibitors, most clinicians believed I knew I was fully aware that I was overlooking older patients. . Gross and his colleagues suspected some doctors would be wary of offering older people this treatment, which could prevent immune cells from switching off and kill cancer cells. . “Maybe they’ll be more cautious,” he said, suggesting interventions for younger patients first.

But in 2018 analysis In more than 3,000 patients, Gross and colleagues found that within four months of FDA approval, most eligible patients for a class of immune checkpoint inhibitor were prescribed the drug. discovered. And the patients who received this treatment in the clinic were significantly older than those in the clinical trials. “Oncologists were very willing to give these drugs to older patients, even if the numbers were not that high,” Gross said.

of another analysisIn a paper published this year, Gross and colleagues investigated how these drugs might help people diagnosed with certain types of lung cancer. The researchers found that the drug increased lifespan by a median of four and a half months in those under the age of 55, but only one month in those over the age of 75.

Gross says there’s no evidence that checkpoint inhibitors won’t help many patients. However, it is important to identify which specific populations are most helped by these drugs. “I thought it would give me more survival benefits than it did,” he says. “This really calls into question how we do our research, and we need to do more research that includes older patients.”

Other types of cancer treatment are ineffective in people over the age of 65.About half of elderly patients with advanced cancer experience severe symptoms and even potentially life threatening Side effects from chemotherapy can lead oncologists to reduce dosages, as was the case with Yedel.

According to Kvale, there is a strong link between lack of evidence from clinical trials and worse clinical outcomes. “There’s a lot of enthusiasm for these drugs that don’t seem to be very toxic at first glance,” she says. It’s so expensive that it’s almost toxic at times. ”

Since the first reports of this data gap, regulators and researchers have worked to resolve the issue. Changes in clinical trials have generally made it easier for older people to participate. For example, fewer and fewer studies have an upper age limit for participants. Last year, the FDA issued guidance recommending that industry-funded trials consider participants with natural age-related declines, include older adults, and relax other criteria. . Still the problem persists.

As Sedrak and his colleagues tried to understand why the needle had moved so little over the past few decades, analysis They found many explanations, starting with eligibility criteria that could falsely disqualify older people. Doctors may also be concerned about whether older patients can tolerate the unknown side effects of new drugs. Patients and caregivers share these concerns. Participation procedures can also pose problems.

“But the main driver, or upstream force, of all this is that trials are not designed with older people in mind,” Sedlak said. Clinical trials tend to focus on survival, and while older people value survival, many people have other motivations and concerns when considering treatment.

Clinical trials are usually aimed at measuring improvement in health and may track tumor size and months of survival. These issues aren’t always top of mind for older people, said Sedlak. He said questions will likely be asked about how the side effects affect a patient’s cognitive function, ability to live independently, and more. “We’re not designing a trial that captures the endpoints that older people want to know,” he says.

Read: Hiccups have an interesting relationship with cancer

As a population, older people experience more side effects, sometimes so severe that treatments rival the disease. In the absence of evidence from clinical trials, clinicians and patients have attempted to find other ways to predict how a patient’s age might affect response to treatment. In the case of Yedel, after discussions with Mr. Kubale and the care team, he opted for a less intensive course of treatment, and since October 2022 his cancer status has remained stable. He still lives in his home and works out with a trainer three times a week.

For those trying to weigh their choices, researchers are developing tools that can take into account a person’s physiological age to create a more complete picture. in 2021 clinical trialSupriya Mohire, a geriatric oncologist at the University of Rochester, and colleagues tested the use of such a tool, known as geriatric assessment, for the side effects and toxicity of cancer treatments. This tool assesses a person’s biological age based on various physiological tests.

The research team recruited more than 700 people, with an average age of 77 years, who were about to embark on new cancer treatment regimens with high risk of toxicity. Approximately half of the participants received guided treatment management recommendations based on geriatric assessments that oncologists considered in their treatment decisions. Only half of this group of patients experienced serious side effects from chemotherapy, compared with 71 percent of those who did not receive professional treatment recommendations.

This kind of evaluation helps avoid both under-treating people who might benefit from chemotherapy and over-treating those who are at risk of serious side effects, Mohire said. It does not compensate for the lack of data on older people. But even in the absence of such evidence, tools such as geriatric assessment can help clinicians, patients, and families make better informed choices. “We’re kind of reversing the problem,” Mohille said. Geriatric oncologists recognize the need for better decision-making methods, but she says, “I think geriatric assessments need to be done until better clinical trial data are available.” says.

Since 2018, the American Society of Clinical Oncology has recommended using geriatric assessment to guide cancer care in older patients. However, clinicians have been slow to follow through with their practice. not necessarily displayed Cancer-specific benefits, such as tumor shrinkage and longer life. Rather, the main purpose of this tool is to improve quality of life. “We need more prospective therapeutic trials in older adults, but we also need to fund all other mechanisms: what should we do for older adults in the real world? We actually know,” Mohire says.