Looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some interventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival.
—Steven D. Mittelman, MD, PhD
"Obesity is associated with cancer mortality,” said Steven D. Mittelman, MD, PhD, at the recent American Association for Cancer Research (AACR) International Conference on Frontiers in Cancer Prevention Research.1 Dr. Mittelman presented a wealth of data to explain the link between obesity and cancer, focusing on leukemia, and suggested there may be a variety of opportunities for intervention to improve survival.
A landmark study by Calle et al2 found that obesity is responsible for more than 90,000 cancer deaths per year in the United States, and according to the American Institute for Cancer Research (AICR), more than 100,000 cancers each year are linked to excess body fat, said Dr. Mittelman, who is Director of the Diabetes and Obesity Program at Children’s Hospital Los Angeles and Associate Professor of Pediatrics and Physiology & Biophysics at Keck School of Medicine, University of Southern California, Los Angeles.
Obesity has been shown to increase cancer incidence, and obese cancer patients experience worse outcomes than lean patients. Retrospective studies have confirmed that children who were obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a significantly higher risk of relapse than their leaner counterparts.
“Leukemia is the most common type of cancer in children, and relapsed leukemia is about the number 6 or 7 cancer in children, so there is a lot of work to be done,” he explained.
“Obesity is not a simple phenotype,” said Dr. Mittelman. Hence, the sheer number of associations and internal and external factors associated with obesity make it difficult to elucidate mechanisms in humans, stressing the need for animal models.
Using mouse models, Dr. Mittelman and colleagues found that obesity accelerates the onset of spontaneous leukemia. Additionally, obese mice implanted with leukemia cells experienced poorer survival after being treated with either vincristine or asparaginase (Elspar), and adipocytes appeared to be at the root of this worse outcome.
Adipocytes attract ALL cells to migrate closer to fat cells. The fat cells absorb the chemotherapy, making the treatment unable to reach the ALL cells and less available in the leukemia microenvironment. Adipocytes also secrete asparagine, glutamine, fatty acids, and other fuels that help leukemia cells survive, allowing them to proliferate and avoid apoptosis. “We think fat cells might be protecting nearby leukemia cells from oxidative stress, which may be part of how they’re protecting them from chemotherapies,” he explained.
Ultimately, Dr. Mittelman and colleagues concluded that adipocytes may contribute to a poorer prognosis in obese patients with ALL and impair their leukemia-related survival. This is cause for particular concern, considering the high prevalence of overweight and obese pediatric cancer patients, particularly among those with leukemia, suggested Dr. Mittelman.
Childhood Obesity and Leukemia
About one-third of children in the United States are overweight or obese. “We’re in Los Angeles, and almost half of our children were overweight or obese at the time of cancer diagnosis,” Dr. Mittelman said.
To further compound this problem, cancer treatment typically leads to weight gain. “In the first month of treatment, these kids’ body fat goes up by 25%,” he observed. This is due to steroid treatment intended to kill the leukemia, which also increases appetite and causes fat accumulation. As a result, high-risk ALL patients experience a sizable and cumulative burden of adipose tissue, which will likely hinder their leukemia treatment and lessen their chances of survival.
Opportunities for Intervention
Evidence suggests that the consequences of obesity may be reversible. A recently published retrospective analysis3 cited by Etan Orgel, MD, also from Children’s Hospital Los Angeles, found that those who were obese at diagnosis but lost weight and became nonobese for more than half the duration of their treatment experienced better outcomes, comparable to their counterparts who were never overweight or obese.
“This implies that the effect of obesity to impair survival is not fixed at diagnosis,” suggested Dr. Mittelman. “The data seem to suggest that intervening might actually help survival. If we were to intervene to try to improve leukemia outcome, at the same time, we would likely (or hopefully) be improving some of these long-term complications.”
In additional laboratory experiments, Dr. Mittelman and his colleagues also found that switching obese mice to a low-fat diet at the onset of ALL treatment greatly improved their survival, giving them better outcomes than the control mice who had been raised on that same low-fat diet. “Considering these data, looking at the clinical outcomes, looking at the mouse data, and knowing what we know about adipose tissue-protecting leukemia cells, I think that some interventions in kids would certainly be justified to see if we can reduce their obesity, slow their gain in body fat, and maybe even improve their survival,” he suggested.” ■
Disclosure: Dr. Mittelman reported no potential conflicts of interest.
1. Mittelman SD: Childhood obesity and leukemia: Opportunities for intervention. AACR International Conference on Frontiers in Cancer Prevention Research. Presented September 30, 2014.
2. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003.
3. Orgel E, Sposto R, Malvar J, et al: Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: A report from the Children’s Oncology Group. J Clin Oncol 32:1331-1337, 2014.