Staging the Aging

Routine assessment of frailty can help clinicians tailor treatments and supportive care to an individual patient’s needs

Hematologic malignancies are often diseases of older adults – with median ages at diagnosis for acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and multiple myeloma (MM) all ranging above 65 years.1

Not every similarly aged patient will have a similar prognosis, though. Finding the optimal treatment for each patient requires careful consideration of an individual patient’s characteristics, life expectancy, the features of the malignancy, and patient preferences (such as goals and personal values).

Most of these factors are easy to evaluate, but a separate, more complicated concept has gained attention as an important measure of patient outcome: frailty.

Frailty is defined as a “vulnerable state that arises from decreased reserve in multiple organ systems, which are initiated by disease, lack of activity, inadequate nutritional intake, stress, and/or the physiologic changes of aging.”2 Its broad constellation of characteristics plays a substantial role in determining how a patient will respond to – and tolerate – treatment. Research suggests that blood cancer patients determined to be frail have poor therapeutic responses, increased toxicities, and worse overall survival.3

“When a patient has been diagnosed with cancer, there is a change in the patient’s health status,” Ashley Rosko, MD, from The Ohio State University Comprehensive Cancer Center, told ASH Clinical News. Dr. Rosko studies cancer and aging, particularly improving outcomes for older adults with myeloma. “We frame a lot of our decisions in oncology on the patient’s perceived ability to tolerate the treatment that [we’re] going to design or prescribe.”

Frailty also is a dynamic quality that can either improve or decline during treatment, and assessing frailty gives hematologists and geriatricians the opportunity to tailor treatment options or institute interventions to improve frailty measures before initiating therapy.

This additional insight is particularly valuable for treating older patients, a population that has historically been under-represented in clinical trials.4 “There is a high prevalence of frailty in an older adult population and yet it’s not measured or characterized in clinical trials,” noted Heidi Klepin, MD, MS, from Wake Forest School of Medicine in North Carolina, whose research focuses on geriatric oncology and minimizing functional decline in older patients with blood cancers. “That’s a major clinical dilemma,” she said.

According to Dr. Klepin, most clinical trials screen heavily for characteristics that could potentially exclude older, frailer patients, either due to their comorbidities or performance status, making it more difficult to find data specific to managing this vulnerable patient population.

ASH Clinical News spoke with Drs. Rosko and Klepin, along with other experts in treating older patients with frailty, to learn more about the condition’s prevalence, the lack of a universal definition, and the implications for treatment.

What Is – and Isn’t – Frailty

Frailty generally is considered a complex syndrome of physiologic decline. It is common among older adults with hematologic malignancies. A recent study found that 42.2% of older adults with blood cancers were considered to be mild, moderately, or severely frail.5 Frailty was more prevalent in women and in patients who were age 75 or older, were diagnosed with leukemia, or had been diagnosed for two years or more.

It also is helpful to define frailty by what it is not. Frailty often is linked with comorbidity and disability, but they are distinct concepts. While comorbidity (defined as the concurrent presence of two or more chronic diseases in an individual) and disability (defined as the need for assistance in activities of daily living) may contribute to the development of or exacerbate frailty, some patients living with well-managed comorbidities would not be considered frail. Conversely, others may have limited but poorly managed comorbidity that makes them frail.

Frailty does appear to affect certain populations more commonly. Large analyses have identified certain risk factors that increase an individual’s likelihood of becoming frail – from gender to race to socioeconomic status. In a report from the National Health and Aging Trends Study, a national longitudinal study of people older than 65, the overall prevalence of frailty was 15.3%.6 However, researchers found that frailty was more prevalent among: women (17.2% of the population, vs. 12.9% of men); racial and ethnic minorities (22.9% of the Black non-Hispanic population and 24.6% of the Hispanic population, vs. 13.8% of the white population); and persons with lower income (25.8% in the lowest-income quartile, vs. 5.9% in the highest-income quartile).

The researchers also suggested the need to develop frailty measures for identifying high-risk subsets or assessment tools that include information about an individual’s ethnicity, access to medical services, and level of social support – rather than relying solely on measures of physical strength – to identify those at risk.

Measuring Frailty

“Frailty is extremely common in our population and it’s very likely underestimated,” said Shahrukh K. Hashmi, MD, from the Mayo Clinic in Rochester, Minnesota and chair of the clinical trials unit at the King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia.

Estimating the prevalence of frailty is complicated by the vast number of assessments used to measure it. There is no single standard tool, and often the measurements are based on a patient’s specific disease.

“There are more than 50 scales published and, at the moment, no one knows [which is] the best scale for [any given] population,” said Dr. Hashmi, who studies the biology of aging in cancer survivors. For example, the International Myeloma Working Group Frailty Score is used exclusively in the MM population, while the Sorror Index evaluates fitness in patients undergoing hematopoietic cell transplantation. (See TABLE for other frailty indexes applicable to hematology patients).

The commonality between most of the measurement tools is the understanding that there are factors “beyond chronological age” that can influence treatment decisions, explained Dr. Rosko.

According to Gregory Abel, MD, MPH, director of the Dana-Farber Cancer Institute’s Older Adult Hematologic Malignancy Program, “the best method to detect frailty is the Comprehensive Geriatric Assessment, an exhaustive functional evaluation performed by a geriatrician.” This test involves looking at a patient’s performance across several domains – including medical conditions, physical function, social circumstances, and environment.7

In the Dana-Farber program, Dr. Abel and staff combine two screening assessments when evaluating patients: the Fried model and the Rockwood model.

The first, known as the “phenotype approach,” assesses frailty by five criteria: unintentional weight loss, self-reported exhaustion, weakness (measured by grip strength), slow walking speed, and low physical activity.8 “This approach has been well-validated as a predictive marker of poor outcomes, including hospitalizations, falls, and mortality, and also is popular because of its clinical reproducibility,” Dr. Abel said.

The Rockwood model views frailty as an “accumulation of deficits” and assesses frailty as the cumulative effect of 30 or more symptoms, signs, diseases, and disabilities.9 At Dr. Abel’s clinic, they have used this method to create a 42-item frailty index. “This model is popular because it can evaluate impairments in many biological systems, is graded, and is conceptually simple,” he noted.

Simplicity and efficiency are key factors to a clinical assessment, according to Dr. Klepin. The Geriatric 8 (G8) health screening tool and the Clinical Frailty Scale – which both include questions about daily functional ability and medical problems – can be particularly useful to risk-stratify patients in a clinical setting and identify patients who require more intensive screening, she said.

“These briefer, shorter, cancer-specific geriatric assessments can be useful in clinical practice,” she said. “If you look at the available data, the strongest signals right now suggest that, at a minimum, assessment of physical function, nutritional status, and comorbidities should be done routinely.”

A recent study published in Blood by Jane A. Driver, MD, MPH, from the Geriatric Research Education and Clinical Center of the U.S. Department of Veterans Affairs, found that a single factor – walking speed – was a reliable indicator of frailty and outperformed other clinical measures like chronological age and cancer type.10 “Despite the availability of many validated tests, few frailty measures have been routinely integrated into general clinical practice due to limited time and resources,” Dr. Driver told ASH Clinical News. “Our work shows that 4-meter gait speed, which takes less than 30 seconds to measure and can be easily obtained with other vital signs, is as valuable a predictor of clinical outcomes as a 15-minute geriatric assessment.”

Age: Just a Number

For decades, evidence has been piling up that, in older patients with hematologic malignancies, a fit or frail status can shape how a patient responds to or tolerates treatments – independent of chronological age.

In one prospective study of older adults with AML, researchers evaluated patients in the areas of cognition, depression, distress, physical function, and comorbidity. They found that, after adjustment for age and disease risk, impaired cognition and physical function were both independently associated with worse overall survival.11

Measures of frailty also can indicate how well a patient may tolerate a given treatment. In the Netherlands, researchers assessed older patients (≥70 years) with NHL using the Groningen Frailty Indicator, a scale that evaluates physical, cognitive, social, and psychological domains of frailty.12 Investigators discovered that patients with an abnormal Groningen Frailty Indicator score were more likely to withdraw early from treatment, in addition to having worse survival.

“Frailty has been validated to be significantly associated with outcomes and independently linked with overall survival, even after adjustment for all the other disease characteristics,” Dr. Hashmi explained.

In particular, Dr. Hashmi identified allogeneic hematopoietic cell transplantation as a crucial setting for patients to be assessed for frailty. “The transplant-related mortality for the procedure is about 20%. That just tells us how poor we are at assessing the physiology and frailty of a patient [who] comes into the clinic for transplant,” he said.

A recent Journal of Geriatric Oncology study by Dr. Rosko and colleagues used the Geriatric Assessment tool to evaluate 100 older patients with MM for frailty before and after an autologous hematopoietic cell transplantation.13 By measuring indicators of frailty before the procedure (such as activity levels, physical functioning, and frequency of falls), clinicians were able to predict the length of a patient’s hospital stay, as well as the likelihood of one-year event-free survival.

Researchers also measured patients’ p16 expression, a molecular biomarker of aging that has been associated with plasma interleuken-6 concentration, a marker of human frailty. Dr. Rosko said they observed a “modest relationship” between p16 in peripheral blood T cells and frailty assessment by self-reported fatigue.

Although the results did not overwhelmingly support the role of p16 as an actionable biomarker, Dr. Rosko said that identifying biomarkers in aging would be like “finding the holy grail” in geriatric research. While researchers continue to explore the role of biomarkers such as cytokines, telomere lengths, and epigenetic markers in aging, they haven’t yet found a single marker indicative of frailty.

“I can’t change that someone is 70 years old, but I can change if [the patient] is losing weight or has low physical function, so … he or she has a better clinical outcome.”

—Ashley Rosko, MD

“It’s an active area of investigation,” Dr. Rosko said. “People are really interested in being able to treat people based upon on their physiologic age and less upon their chronologic age.”

Knowledge Is Power

If a person’s chronologic age is just a number, his or her physiologic age provides a wealth of information with which clinicians can tailor treatment decisions to optimize efficacy or tolerability.

“The more we know about you, and the more we are able to use information like the frailty assessment to predict outcomes, the better we can make an individualized and personalized decision for you,” Dr. Klepin explained.

For example, an older patient with AML who is considered fit, without any markers of poor physical function or disability on assessment tools, may be better positioned to tolerate a more aggressive treatment, like one typically given to a middle-aged patient. A vulnerable or frail patient, however, would have a different treatment goal, Dr. Klepin said. “The ultimate goal may be to focus more on maintenance and quality of life, given their potentially worse treatment outcomes.”

Assessing frailty also can give oncologists the information they need to determine whether an individual could benefit from delaying treatment. In the case of MM, newly diagnosed patients typically undergo three to four rounds of induction therapy before receiving a hematopoietic cell transplantation but, Dr. Rosko said, if a patient is found to have a high frailty score, clinicians could opt to delay the transplant.

“We can wait,” she said. “We don’t have to immediately go to transplant. We can give them some time to optimize their function before the procedure.” If the patient has functional deficits, enrollment in physical therapy could improve their abilities; if they have unintentional weight loss, nutritional supplements or consultation with a nutritionist could reverse the trend, she added.

“I can’t change that someone is 70 years old, but I can change if he or she is losing weight or has low physical function,” Dr. Rosko said. “I can help address those conditions, so when the patient does go into transplant, he or she has a better clinical outcome, meaning a shorter duration of hospital stay and a lower likelihood of relapse or death.”

Knowledge of frailty status allows clinicians to customize supportive interventions according to a patient’s unique needs. “We have a dynamic set of risk factors that we can intervene upon,” Dr. Klepin noted. “An important aspect of frailty assessment is that it can help inform the management and supportive care of that patient.”

A potential danger of measuring frailty is overcorrecting according to an individual patient’s frailty status. If a physician assesses a patient’s physical and mental functioning, as well as environment and social circumstances, and finds the “accumulation of deficits” to be too great, he or she may scale back the treatment approach, inadvertently leading to undertreatment.

Still, experts believe that knowing more about a patient only improves the care the person receives. For example, a patient older than 70 years may be precluded from certain interventions based solely on their chronological age; a frailty assessment may find that the patient is fit enough to receive treatment, despite conventional age limits.

“We feel that routine geriatric screening can ameliorate undertreatment,” Dr. Abel said. “Screening offers an alternative to using age as a proxy for fitness for treatment.”

All patients at Dr. Abel’s clinic are at least 75 years old – the age at which many would traditionally be considered too old for rigorous oncologic regimens because of adverse event risk or quality-of-life concerns.

“Routine geriatric screening programs such as ours can help fit, older adults to receive treatments they would not otherwise receive based on age alone,” he said.

Assess Frailty First

Traditionally, clinical trials’ exclusion criteria weed out patients above a certain age or with high comorbidity burdens, physical disability, or abnormal laboratory results.14 Treatments for hematologic malignancies are approved based on clinical trials in which participants were younger and more fit than their “real-world” counterparts.15 Therefore, frail patients usually receive regimens that were tested in fit patients, which may prove too toxic or have detrimental effects on their quality of life.

A review of the National Institutes of Health clinical trial registry found that, of 1,207 phase I, II, or III trials of treatments for hematologic malignancies recruiting participants, only a small number included patient-centered outcome measures such as quality of life (8%), health care use (4%), and functional capacity (0.7%).16

“Even in blood cancer trials specifically developed for older patients, the primary focus was most often on standard endpoints such as overall survival, while functional and/or patient-reported measures were included in less than one-fifth,” Dr. Abel noted.3 He encourages clinicians to advocate for the inclusion of older patients – accompanied by rigorous frailty assessment – into clinical trials of new agents, giving clinicians applicable data to use in their treatment decisions.

As research suggesting that frailty plays a critical role in determining a patient’s outcome or survival advances, more drug developers are beginning to take notice of its importance. There is increasing interest in identifying treatment options for older patients who have typically been excluded from clinical trials – and even in treating frailty itself as a clinical endpoint.

“For many patients, frailty is a dynamic state,” Dr. Klepin said. “They might start on a treatment pathway when they are ‘robust,’ or at least not frail, but fall into the ‘vulnerable’ category. When they’ve been exposed to certain treatments over time they may transition to a state of frailty. Without having those assessments done over time, we may not recognize that transition, how it should change how we manage patients, or how we interpret the results of a clinical trial.”

Clinical trials are now specifically being designed for patients who are “unfit” or who have comorbidities, Dr. Klepin said, which represents a first step to creating treatment approaches customized for the real-world older adult population. “If we don’t understand the heterogeneity of the patient population and measure it, we’re going to miss the signals in the data that will help us better understand who is at risk for poor outcomes,” Dr. Klepin said.

While Dr. Hashmi believes that oncologists’ and hematologists’ “gut feelings” are important in treatment decision-making, measuring frailty and physiologic age using validated scales is critical in developing treatment approaches.

Still, before frailty assessments are routinely incorporated into trial protocols, investigators must face the same question that clinicians run into in practice: Which frailty scale is the best fit? According to Dr. Hashmi, “We must unite in an effort to evaluate the optimal scale for measuring frailty in hematologic malignancies.” —By Jill Sederstrom


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