Cure for childhood cancer may come at the cost of premature aging

Patient survival is the overarching goal of all cancer treatments, and improvements in survival that have been achieved over the years are an unequivocal victory for oncology.

For children with cancer, advances in therapy can mean the difference between a full life and a tragic death.

Data show that more than 80% of children with cancer will survive beyond 10 years, joining the growing number of childhood cancer survivors as treatments have evolved over the past several decades. However, as the first generation of these survivors reaches middle age, clinicians have begun to witness the long-term consequences of these lifesaving treatments.

Increasingly, unwanted late effects of intensive cancer treatments have underscored the responsibility of oncologists to not sacrifice quality of life for the sake of survival.

Among these effects is premature aging, which manifests as chronic health conditions and frailty. These conditions can, in turn, lead to premature death.

Ongoing studies of long-term childhood cancer survivors have not only allowed researchers to better understand the phenomenon of premature aging, but also have provided unique insight into the mechanisms of the aging process, according to Kirsten K. Ness, PT, PhD, FAPTA, faculty member of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital.

“Childhood cancer survivors can teach us how the cancer and its therapy have contributed to premature aging,” Ness told HemOnc Today. “A patient who is 80 years old who develops lung cancer may also already have heart disease and sarcopenia. However, if a patient is 10 years old and undergoes treatment for leukemia, they don’t have all that other stuff. They’re just a kid. They allow us to ask: What is the contribution of the cancer and its therapy in the frailty phenotype before a patient starts racking up chronic diseases?”

HemOnc Today spoke with pediatric oncologists, survivorship specialists and epidemiologists about how the frailty phenotype manifests in childhood cancer survivors, which treatments may put patients at greatest risk for certain comorbidities associated with older age, and ongoing research into the mechanisms that may cause accelerated aging among both young and elderly patients with cancer.

The frailty phenotype

According to Ness, premature aging among cancer survivors can present itself through a variety of characteristics, many of which are the same as those seen in natural aging.

“Young cancer survivors resemble old people,” Ness told HemOnc Today. “They have muscle wasting, they walk slowly and they spend a lot of time being sedentary. They report feeling exhausted and weak. It might be hard for them to get out of a chair or open a jar. Sometimes they will have the features of old people; they might have gray hair or less hair than you would expect.”

These traits are considered components of frailty, a geriatric syndrome usually observed among adults aged older than 65 years. Marked by exhaustion, slowness, physical inactivity and weight loss, frailty appears in some cancer survivors at significantly younger ages.

Analyzing data from the St. Jude Lifetime Cohort Study, Ness and colleagues identified frailty among 8% of survivors at a median age of 33 years (range, 18-50), compared with 0% of their age-matched peers and 7.2% of adults aged 65 years and older.

“Frailty is an important aspect of aging, and studies of cancer survivors have shown that frailty has occurred in a huge chunk of the population, even in their 30s and 40s,” Shahrukh K. Hashmi, MD, MPH, an oncologist specializing in cancer survivorship and late effects of blood and bone marrow transplant at Mayo Clinic in Rochester, Minnesota, told HemOnc Today. “This is a manifestation of very accelerated aging for these patients.”

The frailty phenotype not only is independently linked to higher risk for mortality among young cancer survivors, but it also may increase their risk for many other complications and toxicities after blood or marrow transplant, according to Mukta Arora, MD, MBBS, MS, professor of medicine in the division of hematology, oncology and transplantation at University of Minnesota and hematologist/oncologist at Masonic Cancer Center.

Among survivors with frailty in the study by Ness and colleagues, 82.1% had at least one, 53.6% had at least two, and 27.8% had at least three grade 3 to grade 4 chronic health conditions. Respiratory, gastrointestinal, liver, genitourinary, neurologic and psychiatric conditions, along with second malignancies, appeared more common among frail than nonfrail survivors.

Ultimately, frailty was associated with an increased risk for death (HR = 2.6; 95% CI, 1.2-6.2) and onset of chronic conditions (RR = 2.2; 95% CI, 1.2-4.2).

“We know that in the community-dwelling elderly population, the frailty phenotype essentially increases their vulnerability to stress and places them at higher risk for mortality, hospitalization and overall just being unwell,” Arora told HemOnc Today. “This has been seen to happen earlier in young survivors of cancer or bone marrow transplant up to age 65 years. They’re developing frailty at the same rate as the community-dwelling elderly.”

Survivors ‘rack up comorbidities’

The premature development of comorbidities normally associated with aging has been observed in various studies of young cancer survivors, including one that spans multiple decades.

Oeffinger and colleagues used data from the Childhood Cancer Survivor Study — a long-term, retrospective cohort study monitoring the health of adult survivors of childhood cancer compared with their siblings — to evaluate chronic conditions among 10,397 survivors diagnosed with childhood cancer between 1970 and 1986 and 3,034 siblings.

Results, published in 2013 in The New England Journal of Medicine, showed that at a mean age of 26.6 years, 62.3% of survivors had at least one chronic health condition compared with 36.8% of siblings at a mean age of 29.2 years, and 27.5% had a severe or life-threatening condition compared with 5.2% of siblings.

Compared with siblings, survivors had more than three times the risk for any chronic condition (RR = 3.3; 95% CI, 3-3.5) and more than eight times the risk for a serious or life-threatening condition (RR = 8.2; 95% CI, 6.9-9.7).

Significant advances in the treatment of pediatric cancer over the ensuing 30 years prompted a second round of recruitments to the Childhood Cancer Survivor Study. This group included about 10,000 survivors diagnosed between 1987 and 1999, as well as 1,000 sibling controls.

In an analysis focused on temporal changes in comorbidities among survivors and siblings, published in 2018 in The Lancet Oncology, Gibson and colleagues evaluated data of 23,601 survivors with median follow-up of 21 years.

Results showed a significant reduction in cumulative incidence of at least one grade 3 to grade 5 chronic condition, from 33.2% (95% CI, 32-34.3) among survivors diagnosed in the 1970s to 29.3% (95% CI, 28.4-30.2) among those diagnosed in the 1980s and 27.5% (95% CI, 26.4-28.6) among those diagnosed in the 1990s. In comparison, the 20-year cumulative incidence of at least one grade 3 to grade 5 condition among siblings was 4.6% (95% CI, 3.9-5.2).

These trends persisted when researchers analyzed survivors by cancer type, with the exception of survivors of medulloblastoma or neuroblastoma, who had higher rates of severe chronic conditions when treated in the 1990s vs. the 1970s.

Those treated in the 1990s compared with the 1970s had lower 15-year cumulative incidence of endocrinopathies (2.8% vs. 5.9%; P < .0001), subsequent malignant neoplasms (1.9% vs. 2.7%; P = .0033), musculoskeletal conditions (3.3% vs. 5.8%; P < .0001) and gastrointestinal conditions (1.5% vs. 2.3%; P = .00037), but a higher rate of hearing loss (5.7% vs. 3% P < .0001).

Although use of new, less aggressive treatment regimens has delayed some of the late effects seen in cancer survivors, premature comorbidities are nevertheless an ongoing problem, according to Gregory T. Armstrong, MD, MSCE, member of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital and principal investigator of the Childhood Cancer Survivors Study.

Source: St. Jude Children’s Research Hospital.

“We know from a number of papers that by the time survivors are aged 50 years, the vast majority will have had one or two life-threatening events,” Armstrong, who also is a HemOnc Today Editorial Board Member, said in an interview. “Even at young ages, they’ve taken on a lot of chronic health conditions. They can walk into clinic at age 30 looking like they’re 60, because they are taking 10 medications and have five or six medical problems.”

Common comorbidities include cardiovascular disease, second cancers, cognitive impairment, growth/hormone problems, bone and muscle issues, fertility issues and more.

“These children have cardiovascular disease at higher rates than their siblings; in fact, cardiovascular disease is the second-leading cause of death among survivors, after getting a second cancer,” Ness said. “The second cancer can be an adult cancer, like breast cancer, colon cancer, lung cancer or melanoma. They rack up comorbidities just like the elderly do.”

Treatment-associated risk

Nevertheless, premature aging and the frailty phenotype do not affect all survivors of childhood cancer.

According to Hashmi, these effects are more likely to occur among patients who have undergone particularly aggressive cancer treatments, such as high doses of radiation and hematopoietic stem cell transplantation.

“Some cancer survivors get chemotherapy or radiation that is five to 10 times more than what a typical patient with cancer would get,” he said. “Patients who undergo bone marrow transplant often receive whole-body radiation or, even if they don’t get radiation, they get chemotherapy doses that are significantly higher.”

Armstrong and colleagues used data from the Childhood Cancer Survivor Study to evaluate long-term effects of radiation treatment. They found that radiation to the brain was a significant driver of comorbidities among both male and female survivors, whereas radiation to the abdomen and pelvis was linked to later medical conditions among men.

Overall, radiation appeared associated with increased risk for late mortality; second neoplasms; obesity; and pulmonary, cardiac and thyroid dysfunction.

Arora referenced the Bone Marrow Transplant Survivor Study, which assessed the prevalence of frailty among 998 younger bone marrow transplant survivors compared with 297 sibling controls. The survivors were more than eight times as likely to be frail compared with siblings. Presence of chronic graft-versus-host disease was most predictive of frailty among allogeneic transplant survivors.

Ness said a more recent study, slated to be published in Journal of Clinical Oncology, showed that a history of lung surgery, amputation of an extremity and exposure to platinum agents were major factors in late effects among childhood cancer survivors.

“We don’t know exactly what the cause is,” she said. “We just know that if a patient receives a DNA-damaging agent during development, that interferes with normal cellular function.”

Armstrong said it is important to ascertain whether premature aging among young cancer survivors is represented by an isolated event or whether it is ongoing and dynamic.

“We want to know whether these patients took a one-time hit and it caused some problems that are static, or whether they are on a downward trajectory that is now completely different than it would have been, such that they are aging faster,” he said. “That is a difficult distinction to make; longitudinal evaluation is required. A cross-sectional evaluation can only tell you where these patients are now.”

Mechanisms of premature aging

Just as the cause and trajectory of premature aging among childhood cancer survivors are not fully understood, conclusive data are lacking regarding the biological mechanisms involved.

In a review article, Ness, Armstrong and colleagues posited five molecular mechanisms of aging that may be induced by childhood cancer treatments: increased cellular senescence, reduced telomere length, epigenetic modifications, somatic mutations and mitochondrial DNA infidelity.

These mechanisms likely are triggered by damage to nonmalignant cells after treatment with radiation or chemotherapy.

“We’ve been investigating these mechanisms in our cohort,” Ness said, adding that they have not yet published their biological data. “Given the resources that we have at St. Jude in terms of our pediatric cancer genome project and the availability of whole-genome sequencing, we were able to look at some of these factors, especially telomere length, mitochondrial copy number and methylation age.”

She said cellular senescence — which she and her co-authors define as “a quiescent state representing the loss of a cell’s ability to replicate or grow” that occurs due to DNA damage from chemotherapy or radiation, among other factors — results in a senescence-associated secretory phenotype (SASP), which is essentially chronic inflammation.

“It’s not like inflammation that occurs after spraining an ankle. It’s more like a smoldering, low-grade inflammation,” she said. “We’re also looking at whether there are elevated levels of the typical cytokines associated with cellular senescence.”

Consequences of cellular senescence can include muscle weakness, frailty, metabolic and cardiovascular dysfunction, increased risk for second cancers, pulmonary fibrosis, an accelerated aging-like state and early death.

Many of the factors Ness and colleagues are exploring are associated with the natural aging process. But they are investigating whether exposure to anticancer therapies may trigger these aging processes among survivors at a much younger age.

For instance, somatic mutations are known to accumulate throughout life and are tied to biologic markers of aging. Ness and colleagues hypothesized that accumulation of these mutations among childhood cancer survivors, whose early-life exposure to DNA-damaging agents may have disrupted genome maintenance pathways, may explain their increased risk for both cancer and accelerated aging.

Also, telomeres, which cap and protect chromosome ends, are known to shorten with age, as well as after exposure to radiation and chemotherapy. This may trigger cellular senescence and its associated sequelae, according to Ness and colleagues.

Researchers also are investigating whether biomarkers of aging in the elderly can be detected among young cancer survivors to predict their risk for premature aging. Among such biomarkers is p16^INK4a, a retinoblastoma protein that has demonstrated increased expression in scalp biopsies taken from survivors of acute lymphoblastic leukemia treated with cranial radiation.

“We’re trying to figure out whether these markers hold true in this population as they do in the elderly,” Ness said.

Late effects in elderly survivors

Being aware of the risks for premature aging related to childhood cancer treatment affords the opportunity to monitor these patients and address these problems early.

However, among older survivors, it may be hard to distinguish between natural aging and aging mediated by cancer treatment, according to a commentary by Armenian and colleagues.

“For older cancer survivors, signs, symptoms and markers of aging largely occur in a background of preexisting comorbidities, making it a challenge to disentangle the contributions of aging and cancer and its treatments on post-treatment health-related outcomes,” the authors wrote.

Ness said the ability to identify and study premature senescence among young childhood cancer survivors will likely provide valuable information on how to anticipate and prevent comorbidities and frailty as patients age.

“The beauty is that we might have a chance to discover what this phenotype is in childhood cancer survivors in their 20s and 30s, before they start to accumulate comorbidities,” she said. “Even though this will eventually happen, it’s not their biggest problem yet.”

A glimpse into the future

The advent of more targeted, less aggressive treatment regimens for various cancers will likely further reduce the burden of premature aging among survivors of childhood cancer, Hashmi said.

“Radiation oncology is much more targeted than it was 20 years ago,” he said. “As far as chemotherapy is concerned, we’re moving toward precision medicine, and with the advent of checkpoint inhibitors and chimeric antigen receptor T-cell therapy, I think we’re moving toward an era of actually modifying and tailoring the therapy toward the individual cancer, rather than shooting in the dark.”

Future research into the frailty phenotype and premature aging will seek to better understand these phenomena and establish effective interventions.

In the meantime, many of the preventive measures for premature aging mimic those of natural aging.

“If we think someone is at risk for this phenotype, then we want to boost their health and well-being, just as we would boost anyone else’s health and well-being,” Ness said. “The only known interventions for accelerated aging in any population are diet and exercise.”

Ness said researchers also are investigating preventive measures for young survivors at risk for specific chronic comorbidities.

“If we know a child is at risk for heart disease, we might give carvedilol,” she said, adding that this is being evaluated in an ongoing study. “We provide children with leukemia with a vibration device that helps prevent bone loss during therapy. There is also a study evaluating high-intensity interval training after radiation therapy to prevent cognitive loss and muscle wasting among children with brain tumors.”

Armstrong said another emerging field of study involves the use of senolytic agents to slow senescence in young cancer survivors. Senolytics are being studied for their potential in selectively triggering senescent cell death.

“James Kirkland, MD, PhD, the head of geriatrics at Mayo Clinic, has five open clinical trials using senolytic agents in various populations,” he said. “He and I are working on a study that isn’t funded yet, looking at these agents in survivors. Researchers are quite keen on these agents in the general population. So, why not consider applying them to survivors in a trial format?”

The ongoing study of premature aging among young cancer survivors seems likely to reap rewards that extend beyond this target demographic — ideally, it will unlock the mysteries of aging itself.

“To my knowledge, this is one of the first times that pediatricians and geriatricians have had to work together to solve a problem,” Armstrong said. “The truth is several of us — pediatricians, pediatric oncologists and epidemiologists — are trying to understand the science of aging by applying the principles to a population that is aging before their time.” – by Jennifer Byrne

Click here to read the , “Should young cancer survivors be preemptively treated with senolytics or other antiaging drugs?”

References:

Armenian SH, et al. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy229.

Armstrong GT, et al. Radiat Res. 2010;doi:10.1667/RR1903.1.

Arora M, et al. JAMA Oncol. 2016;doi:10.1001/jamaoncol.2016.0855.

Gibson TM, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30537-0.

Marcoux S, et al. Radiat Oncol. 2013;doi:10.1186/1748-717X-8-252.

Ness KK, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2013.52.2268.

Ness KK, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2017.76.7467.

Oeffinger KC, et al. N Engl J Med. 2006;355:1572-82.

Pamukcuoglu M, et al. Biol Blood Marrow Transplant. 2019;doi:10.1016/j.bbmt.2019.07.030.

For more information:

Gregory T. Armstrong, MD, MSCE, can be reached at 262 Danny Thomas Place, Memphis, TN 38105; email: greg.armstrong@stjude.org.

Mukta Arora, MD, MBBS, MS, can be reached at 420 Delaware St. SE, Minneapolis, MN 55455; email: arora005@umn.edu.

Shahrukh K. Hashmi, MD, MPH, can be reached at 200 1st St., Rochester, MN 55905; email: hashmi.shahrukh@mayo.edu.

Kirsten K. Ness, PT, PhD, FAPTA, can be reached at 262 Danny Thomas Place, Memphis, TN 38105; email: kiri.ness@stjude.org.

Disclosures: Armstrong, Arora, Hashmi and Ness report no relevant financial disclosures.