Sorafenib toxicity not associated with sarcopenia in radioactive iodine-refractory thyroid cancer
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Adults with radioactive iodine-refractory thyroid cancer and sarcopenia who are treated with sorafenib are no more likely to experience a dose modification due to drug toxicity than a similar patient without sarcopenia, according to findings from an exploratory analysis of the DECISION trial.
“The approval of sorafenib for differentiated thyroid carcinoma was based on results of the phase 3 DECISION trial, in which sorafenib improved the primary endpoint of progression-free survival compared with placebo,” Olivier Huillard, MD, PhD, of the department of medical oncology at Cochin Hospital in Paris, and colleagues wrote in the study background. “Although adverse events with sorafenib were typically grade 1 to 2 and mostly occurred early in the treatment course, rates of dose modifications with sorafenib were higher than in phase 3 trials of sorafenib in renal cell carcinoma and hepatocellular carcinoma. One possible explanation for the increase in toxicity leading to dose modifications with sorafenib in the DECISION trial could be a greater prevalence of sarcopenia following long-term thyroxine suppressive therapy.”
In a retrospective study, Huillard and colleagues analyzed data from 365 adults with locally advanced or metastatic radioiodine-refractory thyroid cancer participating in DECISION, a randomized, double-blind, placebo-controlled trial evaluating sorafenib (Nexavar, Bayer and Onyx Pharmaceuticals; 400 mg twice daily; n = 180) vs. placebo (n = 185). Researchers assessed participants who had CT data at least 30 days before initiating treatment and at follow-up to determine skeletal muscle and lean body mass. Skeletal muscle cross-sectional area was used to determine skeletal muscle index and define sarcopenia. Primary outcomes were changes in mean body weight, BMI and lean body mass from baseline to 6 months; dose modifications within 6 months of treatment initiation, defined as any adverse event leading to a dose modification; early dose modification (first 30 days of treatment); severe toxic events and early severe toxic events (within first 30 days).
Sarcopenia prevalence
Researchers found that 49.4% of participants assigned sorafenib had sarcopenia. However, sarcopenia prevalence varied by geography, ranging from 32.3% for North American participants to 73.3% for Asian participants. Adults who received sorafenib had a lower mean body weight, BMI and lean body mass at 6 months when compared with baseline measurements. Mean weight decreased by 5 kg, mean BMI decreased by 1.8 kg/m² and mean lean body mass decreased by 3 kg.
“For all three measures, the decreases were significantly greater in patients receiving sorafenib than in those receiving placebo (P < .0001),” the researchers wrote.
Dose changes, toxic events
Researchers observed dose modifications for 102 participants assigned sorafenib (56.7%). Median time to a dose modification was 58 days for those with sarcopenia and 140 days for those without sarcopenia. Median time to a severe toxic event was 147 days for those with sarcopenia and was not reached in those without sarcopenia. There were more severe toxic events among participants assigned sorafenib vs. placebo (53.9% vs. 45.6%).
“There was a nonsignificant trend toward a shorter time to dose modifications and severe toxic events in sarcopenic patients compared with nonsarcopenic patients,” the researchers wrote.
The researchers noted that the study was a retrospective exploratory analysis that was not prespecified in the original protocol, and that CT scans were not available for all patients, which could have led to bias.
“Patients with sarcopenia receiving sorafenib have an important risk of toxicity that is not significantly different from that of patients without sarcopenia; no associations were found between sarcopenia and dose modifications or early dose modifications in these patients with differentiated thyroid cancer,” the researchers wrote. “This contrasts with observations in patients with renal cell carcinoma and hepatocellular carcinoma, which showed that sarcopenia was associated with toxicity, which might be attributed to differences in underlying disease and prior treatment.” – by Regina Schaffer
Disclosures: Bayer supported this study. Huillard reports he has received personal fees from Astellas, Genentech, Pfizer, Roche and Sanofi. Please see the study for all other authors’ relevant financial disclosures.
Perspective
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Naifa Busaidy, MD, FACP, FACE
This was a very well-done study with nice data. In the DECISION trial, participants with radioiodine-refractory thyroid cancer assigned sorafenib experienced better progression-free survival compared with placebo. Looking at that study, researchers observed that people who received sorafenib seemed to experience more adverse events when compared against sorafenib studies with other cancers and have wondered why. The theory that drove this new study was that perhaps these patients with thyroid cancer had more sarcopenia, or more loss of muscle mass, and therefore one would experience more adverse events, which led to sorafenib dose reductions.
There are different ways to measure lean body mass, but this outcome was obviously not preplanned when designing the DECISION trial. Here, the authors looked at CT scans the original researchers were conducting every 2 months for these participants anyway for restaging of chemotherapy.
What they found was a larger percentage of the participants in DECISION were sarcopenic at baseline, even before the start of the drug, which is an interesting finding on its own. Then, when participants received sorafenib, some did experience sarcopenia, but those people assigned sorafenib did not necessarily experience more dose reductions or interruptions, at least statistically, vs. those who did not develop sarcopenia.
I thought this was interesting, as I expected them to find that outcome. This could mean there is no association, or it could be a larger number of patients might be needed to show this outcome. If more of the participants assigned sorafenib in DECISION became sarcopenic, might we have seen the association? There is more to this story. It will be important to conduct prospective trials among people assigned sorafenib that assess whether interventions such as weight management and nutrition could help prevent sarcopenia.
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