December 19, 2017
A new review confirms with clinical data what has long been suspected — that long-term cancer survivors age more quickly than their peers.
"We believe that a decline in health that mimics age-related illness is a negative consequence experienced by many recipients of cancer treatment," say the authors, led by Shahrukh K. Hashmi, MD, from the Mayo Clinic in Rochester, Minnesota.
"We have demonstrated with clinical data that cancer survivors develop the health-related manifestations of aging more quickly than their peers. While aging prematurely is a better alternative to dying prematurely, a better understanding of what drives this process presents an opportunity for improvement," the authors write.
The report was published online December 18 in ESMO Open.
On a cellular level, treatment-related tissue damage mimics the phenotypes of aging, either reducing physiologic reserve or accelerating the aging process or both, the team explains.
Although the phenotypic mechanisms underlying accelerated aging have been described previously, few published data link the clinical phenotypes seen in cancer survivors with accelerated aging processes at the cellular level, they continue.
"Our expert review of the associations of cancer treatments with accelerated aging reveals that multiple aging pathways contribute to late complications in cancer survivors," they write.
The interaction between therapeutic exposures and the aging process shortens telomere length, increases the number of senescent cells, and leads to more stem cell exhaustion, primary DNA damage, and abnormal gene activity, Dr Hashmi and colleagues say.
More Needs to Be Done
More needs to be done to address these late complications in millions of cancer survivors currently and to prevent these life-threatening comorbidities in even greater numbers of cancer survivors in the future. "We believe that cancer survivors deserve long-term followup for the mitigation of the late effects."
There are more than 30 million cancer survivors worldwide, the investigators point out. By 2025, an estimated 19 million new cancer cases will be diagnosed each year because of advances in early detection and treatment and the aging and growth of the population. Most patients diagnosed with cancer are now expected to survive.
"Future research to better understand mechanisms of accelerated aging-like phenotypes is essential for the oncology community as well as from a public health and health policy perspective," the study authors emphasize. "The ultimate goal of these studies will be to prevent late complications using early interventions, including lifestyle changes and medications."
Formal cancer survivorship programs to prevent late complications in millions of long-term cancer survivors are not only essential but needed immediately, Dr Hashmi told Medscape Medical News.
"We are now beginning to see the gravity of a multitude of complications among cancer survivors," noted Dr Hashmi. He said more government support for cancer survivorship programs is needed at the federal level. "If we don't act, millions of cancer patients will remain at risk of being lost as they transition from active cancer treatment to maintenance," he warned.
Clinicians must do everything they can to minimize the impact of cancer treatment on the development of comorbidities and other symptoms of accelerated aging, Dr Hashmi said.
"Oncologists should carefully select treatments to optimize cancer-related outcomes and minimize toxicities," he explained. "While patients may receive longitudinal healthcare from many different providers after cancer treatment, minimal toxicities will help those providers in their efforts to maintain patient quality of life."
It's also important for clinicians to encourage cancer survivors to modify lifestyle factors to decrease disease risk, Dr Hashmi emphasized. Survivors should be told to quit all active and passive smoking, limit alcohol consumption, and exercise regularly, he said, adding: "Taking these steps will help reduce the chances of new cancer development and the development of heart disease."
Details of Literature Review
For the study, an electronic search of all available published evidence, including the Cochrane Central Register of Controlled Trials, was carried out in December 2015. A total of 1259 articles on the cellular biology of aging and/or the mechanisms of cancer therapies that mimicked aging were identified.
The review demonstrates that primary cancer drugs are associated with aging-like clinical effects, such as hearing loss, reduced thyroid gland activity, high blood pressure, congestive heart failure, muscular weakness, arthritis, kidney and liver diseases, chronic constipation, and infertility.
Adjuvant long-term corticosteroid treatment is associated with increased risk for cataracts, osteoporosis, nerve damage, skin thinning, infection, and impaired wound healing. Adjuvant tamoxifen chemotherapy is also associated with cataracts, and radiotherapy is associated with dementia, memory loss, carotid artery hardening, and secondary bone marrow cell and blood cancers.
In addition, the findings underscore the fact that survivors of childhood cancer remain particularly vulnerable to the late effects of cancer treatment, even though overall 5-year survival rates have greatly improved, from 20% in the late 1960s to about 80% today.
Review of the Childhood Cancer Survivor Study, for instance, showed that among more than 20,000 five-year survivors of childhood cancer diagnosed between 1970 and 1986, there was a 10.8-fold excess in overall mortality. By 1996, 10% of these survivors had died.
In the St Jude Lifetime Cohort Study, 2.7% of male survivors and 13.1% of female survivors experienced accelerated aging and frailty. The latter was defined as three or more of the following: low lean mass, weakness, exhaustion, low energy expenditure, and slow walking speed. Frailty wasn't seen in any of the age-matched controls.
In the general population, about 10% of individuals age 65 years or older are considered frail (9.6% of women, 5.2% of men), the researchers note.
Frailty was also seen in participants in the Bone Marrow Transplant Survivor Study. A total of 1000 survivors who had undergone hematopoietic cell transplantation had an almost 11-fold increased risk for morbidity, disability, and death due to frailty when compared with siblings.
"We do not wish to suggest that cancer therapies are not valuable or worthwhile; on the contrary, the advances made in cancer treatment have allowed many individuals to live long and healthy lives," Dr Hashmi and colleagues write.
In future, the use of interventions that target the aging process may also play a role, the researchers suggest. Senolytic agents that selectively eliminate senescent cells, and senescence-associated secretory phenotype inhibitors are two of the most promising options currently.
They note that in a variety of animal models of aging and disease, these agents have alleviated frailty, restored progenitor function, reduced insulin resistance, rescued cardiac and vascular dysfunction, decreased adverse effects of radiation therapy, and reduced osteoporosis.
The hope is that in the future, such senolytic agents could be used intermittently, reducing risk for toxicity. Because senescent cells don't divide, resistance is unlikely to develop.
Dr Hashmi and study coauthors have disclosed no relevant financial relationships.
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SOURCE: Medscape, December 19, 2017. ESMO Open. Published online December 18, 2018.