Relationship between sarcopenia and dose-limiting toxicity (DLT) of sorafenib (SOR) in patients (pts) with advanced radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC) in the phase III DECISION trial.

e17594 Background: In the phase III DECISION trial comparing SOR with placebo, pts with advanced RAI-R DTC treated with SOR experienced higher rates of adverse events (AEs) than pts with renal cell carcinoma and hepatocellular carcinoma treated with SOR (Brose et al. Lancet 2014). We hypothesized that long-term thyroxine suppressive therapy might result in a high prevalence of sarcopenia, which is known to be associated with increased toxicity of SOR (Antoun et al. Ann Oncol 2010), and we investigated whether sarcopenia at baseline correlated with DLT. Methods: In DECISION, pts with an analyzable baseline lumbar CT scan were eligible. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured, and the median value for each sex defined the cut-off points for sarcopenia. DLT was defined as any AE leading to dose modification; early toxicities occurred ≤30 days after treatment initiation. Results: Of 365 eligible pts, 199 (55%) were sarcopenic (SOR n = 100, placebo n = 99) with large geographic differences: 65/91 Asians (71%), 29/62 North Americans (47%), and 105/212 Europeans (50%). Sarcopenia was 3-fold more frequent than non-sarcopenia in pts ≥75 years of age (19% vs 6%) and was associated with lower body weight (mean [standard deviation]: 71.3 [16.8] vs 80.8 [19.5]; P < 0.0001). Among SOR pts, 76/180 (42%) experienced early DLT of which 44/76 (58%) occurred in sarcopenic pts (P = 0.6497). Among the 90 males, 61 (68%) were sarcopenic and of the 35 males with early DLT, 27 (77%) were sarcopenic. Median time to DLT in sarcopenic vs non-sarcopenic pts who received SOR was 63 vs 95 days, respectively (log-rank P = 0.5328). Conclusions: In this exploratory analysis from DECISION, approximately half of the pts were sarcopenic. In the overall population, no association between sarcopenia and early DLT or DLT were found. Clinical trial information: NCT00984282.

Safety and tolerability of sorafenib in patients with radioiodine-refractory thyroid cancer

Effective adverse event (AE) management is critical to maintaining patients on anticancer therapies. The DECISION trial was a multicenter, randomized, double-blind, placebo-controlled, Phase 3 trial which investigated sorafenib for treatment of progressive, advanced, or metastatic radioactive iodine-refractory, differentiated thyroid carcinoma. Four hundred and seventeen adult patients were randomized (1:1) to receive oral sorafenib (400 mg, twice daily) or placebo, until progression, unacceptable toxicity, noncompliance, or withdrawal. Progression-free survival, the primary endpoint of DECISION, was reported previously. To elucidate the patterns and management of AEs in sorafenib-treated patients in the DECISION trial, this report describes detailed, by-treatment-cycle analyses of the incidence, prevalence, and severity of hand–foot skin reaction (HFSR), rash/desquamation, hypertension, diarrhea, fatigue, weight loss, increased serum thyroid stimulating hormone, and hypocalcemia, as well as the interventions used to manage these AEs. By-cycle incidence of the above-selected AEs with sorafenib was generally highest in cycle 1 or 2 then decreased. AE prevalence generally increased over cycles 2–6 then stabilized or declined. Among these AEs, only weight loss tended to increase in severity (from grade 1 to 2) over time; severity of HFSR and rash/desquamation declined over time. AEs were mostly grade 1 or 2, and were generally managed with dose interruptions/reductions, and concomitant medications (e.g. antidiarrheals, antihypertensives, dermatologic preparations). Most dose interruptions/reductions occurred in early cycles. In conclusion, AEs with sorafenib in DECISION were typically grade 1 or 2, occurred early during the treatment course, and were manageable over time.