1. DiGiulio, Sarah

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New research has shown that the prevalence of frailty in young adult survivors of childhood cancers is similar to that of adults 65 and older, according to new data from the St. Jude Lifetime Cohort Study published in the December 20 issue of the Journal of Clinical Oncology (2013;31:4496-4503).

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"These rates, particularly among women in this cohort, are similar to the prevalence of frailty in an elderly population three decades older," said the study's corresponding author, Kirsten K. Ness, PhD, PT, Associate Member in the Department of Epidemiology and Cancer Control and of Pediatric Medicine at St. Jude Children's Research Hospital.


The findings are significant, she added, because the phenotype is associated with increased risk of developing another chronic illness, and an increased risk of death.


Previous research has shown that in comparing certain outcomes (such as cardiorespiratory fitness) in childhood cancer survivors with those outcomes in the general population, survivors often look like individuals who are 20 to 30 years older, explained Kevin C. Oeffinger, MD, Director of the Adult Long-Term Follow-Up Program at Memorial Sloan Kettering Cancer Center and a member of the Departments of Medicine and Pediatrics there.


"Dr. Ness's study is the first in-depth study using a group of accepted measurements to define frailty (accelerated aging) and apply this across a large population of childhood cancer survivors," he said via email. Observing the increase in frailty and prefrailty, the obvious question we all have is how preventable this outcome is."


Study Details

Ness and her colleagues analyzed the rates of frailty in the patients who were members of the St. Jude Lifetime cohort, which includes childhood cancer survivors treated at the institution between 1962 and 2003, who are 18 or older and at least 10 years from their original cancer diagnosis. Patients were defined as frail if they met three or more of the following criteria (and prefrail if they met two):


* Low lean muscle mass (no more than 1.5 standard deviations below age-, sex-, and race-specific values from the National Health and Nutrition Examination Study);


* Exhaustion (scores 1.3 standard deviations below the population mean of 50 on the vitality subscale of the Medical Outcomes Survey Short Form-36);


* Low energy expenditure (for men, expenditure less than 383 kilocalories per week, and for women, expenditure less than 270 kilocalories per week);


* Slowness (for women less than 159 centimeters tall and men less than 173 centimeters tall, taking 7 seconds or more to walk at their usual pace for 15 feet; and for women 159 centimeters or taller and men 173 centimeters or taller, taking 6 seconds or more to walk at their usual pace for 15 feet); and


* Weakness (as determined by sitting hand-grip strength test with a dynamometer).



In the cohort of 1,922 eligible survivors, 13.1 percent of female participants and 2.7 percent of male participants met the criteria for frailty; and 31.5 percent of the female participants and 12.9 percent of the male participants met the criteria for prefrailty. The patients' average age was 33.


In the comparison population of participants without a history of cancer, no individuals met the criteria for frailty, and 4.6 percent of the male participants and 7.8 percent of the female participants met the criteria for prefrailty. Among the survivors, the prevalence of frailty and prefrailty increased with age, and the trend was more apparent in women.


Additional findings from the study were:


* The combined prevalence of frailty and prefrailty was highest among patients who had had central nervous system tumors (41.2 percent), soft tissue sarcoma (39.4%), and other solid tumors (38.7%);


* Approximately 30% of the survivors of leukemia, lymphoma, and bone tumors were prefrail or frail;


* Among the 1,922 members of the study cohort, there were 31 deaths after the first clinical assessment-4.6 percent among participants with and 1.4 percent among those without the frailty phenotype; and


* In the cohort, frail male survivors were six times more likely to die than non-frail male survivors, whereas frail female survivors were twice as likely to die as non-frail female survivors.



Causes of Frailty

Ness noted that because of the limited number of events following the baseline assessment of frailty, it was not possible to evaluate the risk of early frailty based on cancer diagnosis, treatment, and length of follow up. But, the treatment-related risk factor most associated with frailty was cranial radiation.


"It could be that just having had chemotherapy or just having had cancer [causes the increased risk of frailty]," she said. Additionally it could be that cranial radiation affects the pituitary gland and decreases the levels of growth and steroid hormones responsible for muscle development, she said. "It's also possible that this problem is just hormonal."


Additional research is needed to further understand sex-specific biology and pathophysiology to determine which childhood cancer survivors are at higher risk for being frail to target with interventions, Ness said. Another next step is assessing what muscle looks like in these populations-and then designing interventions to increase muscle mass: "Is the muscle mass problem starting way back, and the survivors never recover it completely, causing them to have abnormal muscle mass? Or, is it that they develop a sedentary lifestyle as a result of having cancer?


"We're doing biology studies in the survivors who are frail to compare them with non-frail survivors and healthy controls."


Prevalence Concerning

Asked for her opinion, Lisa Diller, MD, Chief Medical Officer at the Dana-Farber/Boston Children's Cancer Center and Medical Director of the David B. Perini, Jr. Quality of Life Clinic there, explained that because research has shown that childhood cancer survivors have a higher risk of chronic illness and for having multiple chronic illnesses, it's not surprising to see early frailty in this population. "But, the prevalence was surprising," she said. "And the findings make me concerned that handling conditions later on-osteoporosis, renal dysfunction, and debilitating arthritis, and other diseases of the elderly-will be difficult for this population."


Diller agreed with Ness that understanding the genetic phenotype associated with frailty risk will be an important next step in this research. "If we knew that a certain treatment was associated with a certain genotype to develop into a significant chronic illness or frailty later in life, we might try to figure out ways to use an alternative therapy."

KEVIN C. OEFFINGER, ... - Click to enlarge in new windowKEVIN C. OEFFINGER, MD. KEVIN C. OEFFINGER, MD: "The obvious question we all have is how preventable this outcome is."

The other factor to consider, Diller added, is adaptation to illness. "You're talking about a really long latency time from when the patient was treated until when the patient was measured. What happens in the time between completion of treatment and this observation [for the study] impacts the individual's frailty," she said. "Asking questions about exercise, lifestyle choices, socioeconomic factors, social support, employment, and education-the other factors besides an underlying genotype-would be an important next study."


The changes in treatment of childhood cancer patients over the last 40 years should also be considered, Diller noted. Many of the patients in the study were treated in the late 20th century and their therapies may not be representative of the survivors we'll be seeing in the next couple of decades, she said.


"Many of the patients were treated with more radiation than is used now. And many of the treatments known to cause significant disease in childhood cancers survivors-we've tried to eliminate or reduce as much as possible. We're hoping the changes will result in fewer late effects, including less frailty."

LISA DILLER, MD. LIS... - Click to enlarge in new windowLISA DILLER, MD. LISA DILLER, MD: "The findings make me concerned that handling conditions later on-osteoporosis, renal dysfunction, and debilitating arthritis, and other diseases of the elderly-will be difficult for this population."

The Takeaway

For now, the takeaway is that young cancer survivors should do the things known to optimize muscle mass and muscle strength, Ness said. "Eat a healthy diet with adequate amounts of protein and fat (and not too much junk food), and get exercise."