It has been known that children with acute lymphoblastic leukemia (ALL) at extremes of weight at diagnosis—underweight or obese—have worse event-free survival outcomes than similar patients in normal weight ranges.
Now, a large retrospective study shows that improving weight during therapy—increasing or decreasing, respectively—improves outcomes to the point where they are comparable to those of patients who had never been obese or underweight.
The rate of treatment-related toxicities also drops as weight is normalized.
If the results of the study—published in the Journal of Clinical Oncology (2014;32:1331-1337)—are validated, weight normalization would be a modifiable risk factor in pediatric ALL, and perhaps the only one.
Multiple mechanisms are likely involved, the researchers said. “Children who stay underweight have difficulty tolerating their therapy, they are prone to infection—particularly fungal infections—and pulmonary toxicities, and they need more transfusions and supportive care so they may not receive all their medication,” explained the first author, Etan Orgel, MD, Assistant Professor of Clinical Pediatrics at the University of Southern California and Attending Physician at Children's Hospital of Los Angeles and the Jonathan Jaques Children's Cancer Center at Miller Children's Hospital.
“In obese children the toxicity seems to be to the liver and pancreas,” he said in an interview. “The obese are already at risk for toxicities in the liver and pancreas, possibly due to the effect of adipose tissue on those organs, and it fits into the clinical picture that giving them chemotherapy could have a combined effect.”
The new study is based on data from the Children's Oncology Group CCG-1961 study—Nachman JB et al: JCO 2009;27:5189-5194—of 262 patients showing that young adult patients with ALL who had a rapid response to induction chemotherapy benefited from early intensive post-induction therapy but not from a second interim maintenance and delayed intensification phase.
Using weight data from CCG-1961 on 2,008 patients who underwent 13,946 courses of therapy, the researchers in this new study found that patients who were obese or underweight at diagnosis and for 50 percent or more of the time between the end of induction and the start of maintenance therapy had event-free survival rates similar to those of patients in the normal weight ranges, with hazard ratios of 1.43 and 2.30, respectively.
The five-year event-free survival rates for patients obese or underweight at diagnosis were 64 and 65 percent, respectively, as compared with 74 percent for patients who had normal weight or were overweight.
“Both of these are modifiable and addressable risk factors,” Orgel said. “The caveat is that these children are going through very intensive therapy that affects their mobility and appetite, and many other factors, so we have to address their weight in that context.”
He said that in his practice, the findings will make him be a lot more aggressive for treatment of children who are underweight because there are ways to help them gain weight—“medicines to stimulate their appetite, calorie supplements, and shakes, even using tube feedings. We can't say ‘they’re going through so much, just let them eat what they want.'”
Dealing with the obese child might be more of a social problem, he continued. “For obese children, we enter the territory of treating the family, and using health promotion behaviors that encourage activity and healthy diet and healthy weight loss. There is an epidemic of obesity that's being recognized across society, but in treating pediatric leukemia we have to address this even while we are giving them medicines that might make improving weight difficult.”
In an accompanying editorial (JCO 2014;32:1293-1294), Paul C.J Rogers, MD, Clinical Professor in the Division of Pediatric Oncology/Hematology/BMT at British Columbia Children's Hospital and the University of British Columbia, noted that prior studies have looked at the impact of weight on outcomes in pediatric leukemias, but this is the first comprehensive evaluation of the impact of changes in weight during therapy. The new data will hopefully have a positive effect, in that clinicians will evaluate nutrition more comprehensively than is standard practice, he said.
Standard practice, though, is not all that uniform, said Rogers, a former chair of the Children's Oncology Group Nutrition Committee, who also coauthored a 2008 survey across all COG institutions looking at the practice of nutritional evaluation and intervention (Rogers PC et al: Pediatr Blood Cancer 2008;50 [suppl 2]:447–450). “As expected, there was no consistency or uniformity,” he said.
Commenting on the new study, Rogers noted that it uses weight as the main criteria: “Weight as an acute indicator of under- or over-nutrition is not accurate, because in small children, any fluid shifts—dehydration or overhydration—will affect weight. Rather than weight or BMI, we would prefer to evaluate under-nutrition with the triceps skin folds measurement and mid upper arm circumference.”
Another possible drawback to the study, he said, was that it was retrospective rather than prospective, although that was necessarily a significant drawback in this type of study. “We want people to evaluate weight change as a prognostic factor in all future clinical trials, and look at weight change on a routine basis as patients are being treated on study as well as off study.”
Could Be Practice Changer
Also asked to comment on the study for this article, L. Kate Gowans, MD, Section Head of Pediatric Hematology and Oncology at Beaumont Children's Hospital in Michigan, said the study “could be a practice changer for a lot of us—it may have identified a modifiable risk factor that's been there for some time but the question hasn't been asked. For all of the things about their leukemia that can't be changed, is this finally a modifiable risk factor that we as physicians can be working on sooner rather than later to improve outcomes? Do we sit down and have a policy discussion about whether to be more aggressive and not wait until there is a 10 percent loss of body weight before we intervene?”
Gowans estimated that 75 percent of ALL patients begin therapy at a normal weight. And while the prototypical picture of the childhood leukemia “poster child” is thin and weak, with no hair and having trouble getting by day to day, in reality such patients typically look healthy and are at normal weight, she said.
“Between months two and six when therapy intensifies, that's when we start to see extremes, particularly at the low end.”
On the overweight end of the spectrum, some children undergoing therapy for leukemia put on weight and keep it on. “When most of them are on steroids, they gain weight, and when they come off steroids, the weight comes off,” she said. “But there is a distinct subset of kids who develop a metabolic syndrome after the steroid exposure and they stay overweight and get more overweight even if they are off therapy. Perhaps we need to identify these patients earlier on and get more aggressive about weight loss while they're on therapy,” she said.
Gowans acknowledged that could be a tough sell to parents, when their children are already going through so much. “But maybe now [with these new data] we can tell the parents that if we don't address the children's weight right now, they can be at a higher risk for the leukemia coming back. This might be what is needed to get parents to cooperate.”
Will Guide Nutritionists
Also asked for her perspective, Lisa G. Roth, MD, Assistant Professor of Pediatrics in the Division of Pediatric Hematology/Oncology at Weill Cornell Medical College, said that underweight and obesity both can lead to variations in chemotherapy dose and pharmacokinetics.
Currently there is no good consensus on how to dose chemotherapy for patients who are overweight, she noted. “Sometimes they are dosed according to ideal versus actual body weight, and that might have an effect as well.” She said she will definitely discuss this paper with nutritionists at Weill Cornell—“this will very likely have an impact on their recommendations and guidance for nutritional interventions.”