Cranial Radiation Ups Obesity Risk After Childhood Cancer

Childhood cancer survivors are more likely to be obese than other people of the same age, sex, and race without a history of childhood cancer, a new population-based study confirms.

In particular, cranial radiation for childhood cancers appears to have the greatest influence on obesity in adult life, with 47% of those who received this form of treatment becoming obese, vs 29.4% who did not.

The presence of obesity at cancer diagnosis also affects outcomes, as do age at diagnosis and the presence of polymorphisms in genes responsible for neural growth, repair, and connectivity in patients who received cranial radiation.
The study was published online May 11 in Cancer. Lead researcher Carmen Wilson, PhD, from St Jude Children’s Research Hospital, Memphis, Tennessee, told Medscape Medical News, “These results are important because obesity is associated with an increased risk of premature death and a variety of health problems, including cancer and heart disease.”

She also pointed out that the findings stem from “one of the most comprehensive studies yet of obesity in childhood cancer survivors”; of the almost 2000 survivors in the study, “36.2% had a body mass index [BMI] of 30 kg/m2 or more [during 25 years of follow-up], which is defined as obese.”

And she emphasized that the long-term goal of the St Jude research group is to develop effective weight-management strategies for the growing population of childhood cancer survivors in the United States.

Reflecting on the paper, which he found both “fascinating and provocative,” Gerald Denis, PhD, associate professor of pharmacology and medicine, Cancer Research Center, Boston University School of Medicine, Massachusetts, said the results demonstrate the challenges of minimizing the risk of obesity while treating the childhood cancer.

The latter is understandably the priority given the lack of certainty that patients will go on to develop obesity, “but the concern here is partly disciplinary: they [oncologists] are not licensed to treat obesity later in life.”
“Still, in light of these new data, it would be helpful for the professional societies to formally discuss the relative risks and benefits of whether to avoid cranial radiation for any cancer in children unless absolutely necessary,” he commented.

Childhood Cancer Survivors Followed up for 25 Years

Prior studies have identified a high risk of obesity among childhood cancer survivors, particularly those exposed to cranial radiation, and there is also evidence that genetic variation can modify this risk.

In view of these findings, Dr Wilson and colleagues set out to examine factors influencing adult obesity among those included in a register of patients previously treated at St Jude Children’s Research Hospital. In total, 1996 childhood cancer survivors who had received treatment and had survived for over 10 years from diagnosis were included. Their median age at diagnosis was 7.2 years, median age at follow-up was 32.4 years, and median follow-up time was 25 years.

Over a third of individuals (36.2%) were obese at a median follow-up of 25 years after diagnosis; this was 14% higher than the rate in an age-, sex-, and race-matched population drawn from National Health and Nutrition Examination Survey (NHANES) data (31.6%).

The risk of obesity was greatest for those were older at evaluation (≥ 30 years vs < 30 years; P < .001) and those whose pediatric cancer treatment included cranial radiation (P< .001) and chemotherapy with glucocorticoids (P = .004), Dr Wilson and colleagues say.

Patients aged 4 or younger when their cancer was discovered were more likely to be obese than survivors who were older when their cancer was found (40.4% of male and 39.5% of female survivors with a diagnosis before age 5 years were obese).

The researchers also identified genetic polymorphisms in regions near or within the FAM155A, SOX11, CDH18, andGLRA3 genes that may increase the odds of obesity among survivors who received cranial radiation.

Abdominal Radiation Appears to Be Protective

Obesity also differed by cancer type. Over 25% of lymphoma or solid-tumor survivors (excepting females with renal cancer) were obese, compared with 43% of lymphoblastic leukemia survivors.

By gender and cancer type, the highest prevalence of obesity was seen among males who had survived leukemia, at 42.5%, while those who had been treated for other tumors had an obesity prevalence of 38.8%. Among women survivors, the highest prevalence was seen in survivors of neuroblastoma, at 43.6%, and of leukemia, at 43.1%.

But those treated with chest, abdominal, or pelvic radiation were only about half as likely to be obese as other survivors (22.4% vs 40.7%, odds ratio [OR] = 0.48, P < .001); this was regardless of whether they had received cranial radiation or not (P < .0001).

With regard to these findings, Dr Denis said: “It is fascinating that abdominal radiation was inversely associated with obesity. Perhaps visceral adipogenesis was affected because the preadipocytes were ablated due to radiation exposure, whereas subcutaneous preadipocytes elsewhere in the body that were not exposed remained unaffected.

“Additional information about body composition and metabolic parameters would be very helpful to understand the possible mechanisms,” he added.

Cranial Radiation: Does It Damage Hypothalamus?

Dr Wilson hypothesized that the higher prevalence of obesity among childhood cancer survivors who received cranial radiation could be “radiation-induced damage to the hypothalamic-pituitary axis, leading to alterations in leptin sensitivity or growth-hormone production.

“However, this remains to definitively established,” she observed.

And Dr Denis questioned the use of cranial radiation in some patients — specifically those diagnosed with renal cancer or leukemia — and noted that data on whether brain metastases were present or not would have been helpful.

“It would be useful to have more information about the specifics of the cases, because unless it is obvious that the patient requires cranial radiation for a brain tumor, this is clearly a bad idea from the standpoint of obesity risk,” he commented.

He added that it would also be helpful to delve further into the cases of those who survived childhood cancer and were exposed to cranial radiation but who did not become obese later in life.

“Do these patients have protective factors? Could a mechanism be identified that would lead to a novel chemoprotective agent that should be administered to all patients who are about to undergo cranial radiation to reduce their risk for obesity?” he asked.

“These observations will be important for clinical and radiation oncologists to appreciate.”

Genetic Findings May Help Tailor Cancer Treatment in Kids

This study is also one of the first to explore how genetics may affect obesity in childhood cancer survivors, Dr Wilson told Medscape Medical News.

“The four regions of genetic variation identified as being associated with obesity in survivors treated with cranial radiation could lead to better methods of managing obesity risk in young cancer patients during and after treatment,” she observed.

The strongest observed link was near FAM155A, a region previously associated with an increased percentage of fat mass in children of Hispanic descent and with anorexia nervosa.

“Although little is known about the function of FAM155A, it is expressed in the hypothalamus and pituitary, consistent with the hypothesis that [cranial radiation] may modify the risk of obesity among survivors by disrupting the hypothalamic-pituitary axis,” she commented.

Weight Management in High-Risk Groups

In conclusion, Dr Wilson remarked that their results suggest the high prevalence of obesity among survivors of childhood cancer persists many years after cancer therapy and that “the likelihood of a survivor being obese in adulthood may be influenced by the type of therapy they received and whether or not they were obese at diagnosis.”

She emphasized that individuals who care for survivors of childhood cancer “should be aware that the risk of obesity is increased among certain subpopulations of survivors, particularly those treated with cranial radiation and glucocorticoids,” adding that “the findings highlight the need for the development of effective counseling and weight-loss interventions designed to meet the unique needs of childhood cancer survivors.”

And with respect to the genetic associations, “the ability to identify patients at increased risk of obesity on the basis of genetic susceptibility may improve early detection of high-risk subgroups,” she and her colleagues conclude.

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