SAN DIEGO—Patients with advanced medullary thyroid cancer appear to experience rapid loss of skeletal muscle mass when treated with the tyrosine kinase inhibitor cabozantinib, researchers reported here at ENDO 2015, the Annual Meeting of the Endocrine Society.
“Cabozantinib-induced weight loss appears to be related not only to its gastrointestinal effects but also to an independent mechanism that leads to early-onset skeletal muscle and adipose tissue loss,” reported Lily Kwatampora, MD, MPH, a fellow in endocrinology at Baylor College of Medicine, in her poster presentation.
In the study, she and her colleagues found that three months after the start of treatment with cabozantinib, 60 percent of 21 patients identified as having progressive medullary cancer had a weight loss of more than five percent (Grade 1), which corresponded to a loss of at least one kilogram of skeletal muscle in 45 percent of patients.
“These losses were more pronounced at 12 months,” she said, illustrating that of the 15 surviving patients in the retrospective study, just one patient had gained weight; three had experienced Grade 3 weight loss (more than 20 percent); five others had Grade 2 weight loss (more than 10 percent); and two patients had Grade 1 weight loss.
Skeletal muscle changes followed a similar pattern, with nine of 20 patients analyzed having greater than a five percent decrease in skeletal muscle mass at three months; and 11 of 15 survivors exhibiting greater than five percent skeletal muscle loss at 12 months.
Four of the 21 patients did not report any diarrhea but had weight loss; two of those patients reported nausea and anorexia. “Of the other two patients who did not report nausea, anorexia, or diarrhea, one had the most profound body composition changes, becoming sarcopenic after only three months,” Kwatampora reported.
“Further studies are needed to better understand these independent effects, with the goal of intervening early to prevent deterioration into sarcopenia and cachexia, which impact treatment outcomes and survival.”
‘Expands on Known Side-Effects Profile’
Asked for his opinion, Jason Wexler, MD, Clinical Assistant Professor of Medicine at Georgetown University and an attending endocrinologist at MedStar Washington Hospital Center, said: “This is important information that expands on the known side-effects profile of cabozantinib, which can be very difficult to tolerate for these patients.
“When you put this in the context of the seriousness of this disease, I don't think that it means you wouldn't use these drugs in the appropriate circumstances. This study highlights that physicians who are treating patients need to be aware of this particular side effect, not only because of its effect on the patients, but because it may make these patients less likely to respond well to the treatment.”
Intervention to mitigate the effects of cabozantinib on muscle and weight loss could include a variety of modalities, Wexler continued. “We might try dose reduction, or we could get these patients early to a cancer-focused dietitian to make sure they are able to maintain proper caloric intake; or we might try to get them into some exercise program so they don't lose muscle mass and waste away and deteriorate. If that happens they have to come off treatment, and that may accelerate the course of the disease.”
He said that the weight loss and muscle loss experienced by the patients in the study may well be due to some mechanism of action of the tyrosine kinase inhibitor because the impact appeared to occur rapidly and robustly, despite, in some patients, the absence of gastrointestinal discomfort.
“Even though medullary thyroid cancer is a bad cancer, the time course in which patients with the disease develop that wasting syndrome is a much slower, drawn out process” Wexler said.
“I think that the changes they are seeing here are more profound than seen earlier in the disease. I think these changes are much too robust and much faster than you would expect than what would be seen with the natural history of the disease.”
Kwatampora noted that previous studies have indicated that cabozantinib—approved by the Food and Drug Administration because it has shown to improve progression-free survival in patients with progressive medullary thyroid cancer—is associated with weight loss.
“Although this may partly result from gastrointestinal adverse events such as diarrhea and anorexia, recent evidence suggests a direct inhibition on protein synthesis and on adipose tissue by inhibition of adipogenesis. Skeletal muscle loss—sarcopenia—is linked to poor functional status, decreased treatment response, and reduced overall survival.”
Context Important: ‘These Patients Are in Worst Shape’
Wexler pointed out that cabozantinib is a standard treatment for medullary thyroid cancer and that patients who are candidates for a tyrosine kinase inhibitor like cabozantinib are in the worst shape—“These are patients who have progressive metastatic disease. These are patients who are going to die of their disease. Obviously, the risk and benefit of every drug used to treat them has to put in the context of having a fatal disease. There is no question that these drugs have lots of side effects. In many patients they can be really tough to tolerate.”
Kwatampora noted that treatment with cabozantinib—despite its adverse effects—has shown to double the time to disease progression.
To describe the impact of cabozantinib on body composition in patients with advanced medullary thyroid cancer, the researchers performed a retrospective analysis of patients with progressive medullary thyroid cancer treated with cabozantinib between 2006 and 2014 at the University of Texas MD Anderson Cancer Center, collecting data on weight, height, gastrointestinal-related adverse effects, dose adjustments and tumor response during the first 12 months of therapy.
A total of 17 men and four women were included in the study, with a median age of 52, and a range of 36 to 71. Median body mass index at baseline was 28 kg/m2, and 13 of the patients in the study were considered to be either overweight or obese at the beginning of their treatment with cabozantinib.
Abdominal computer-assisted tomography scans were performed to monitor response. Cross-sectional images of the third lumbar spine were used to measure skeletal muscle and visceral and subcutaneous adipose tissue surface area changes.
“Despite most patients falling within ‘normal’ or ‘overweight’ body mass index categories, more than half were sarcopenic during the 12 months of therapy,” Kwatampora stated. “This is contrary to the assumption that most advanced thyroid cancer patients are relatively healthy compared with patients with other advanced cancers.
“While our study is limited by small sample size and no comparison group, these findings are similar to other studies investigating tyrosine kinase inhibitor related weight loss in other cancers.”
“This study is the first to demonstrate cabozantinib's effects on body composition in advanced medullary thyroid cancer patients,” the researchers reported. “Understanding these effects on body composition will guide identification of at-risk patients, dose selection at initiation of therapy, and identification of patients who would benefit from interventions to decrease sarcopenia.
“We hope that ultimately ameliorating this adverse event would improve tolerance to therapy, decrease treatment interruptions, and early withdrawal from treatment.”