Durham, NC (PRWEB) April 15, 2014
A new study published in The Oncologist journal shows that a subset of patients with advanced differentiated thyroid cancer (DTC) and multiple comorbidities in which full-dose sorafenib is considered unsafe can initiate treatment with sorafenib at lower starting doses without adversely affecting efficacy or tolerability compared with full-dose sorafenib. A team of researchers led by Ramona Dadu, MD, at the MD Anderson Cancer Center in Houston, TX, performed a retrospective analysis to evaluate the relationship between sorafenib starting doses and first-line treatment tolerability and efficacy.
“Our data suggest that treatment with sorafenib, when administered by experienced specialists outside of a clinical trial setting, resulted in similar efficacy and tolerability as previously reported in clinical trials,” Dr. Dadu said. “But, most importantly, we showed that the efficacy and tolerability of sorafenib in treatment-naïve DTC patients does not appear to be negatively influenced by lower starting daily doses.”
Sorafenib is an orally active, multi-tyrosine kinase inhibitor (TKI) used in the treatment of advanced renal cell carcinoma and unresectable hepatocellular carcinoma. In November 2013, sorafenib also became the first targeted agent approved for the treatment of advanced DTC. In current practice, sorafenib is the most frequently used first-line TKI in patients with progressive, radioactive iodine (RAI)-refractory DTC.
Although the recommended dose of sorafenib is 800 mg daily (400 mg twice daily) in solid tumors, no patients with thyroid cancer were included in the phase I dose-finding trials. In phase II trials of sorafenib 800 mg daily in patients with advanced, RAI-refractory DTC, up to 79% of patients required dose reductions, and up to 25% discontinued treatment due to toxicity. In a phase III trial of patients with TKI-naïve DTC, sorafenib 800 mg daily improved progression-free survival by 5 months compared with placebo, but patients required frequent dose reductions (64%), dose interruptions (66%), or discontinuation due to toxicity (19%). By comparison, in a small trial of DTC patients treated with sorafenib 200 mg twice daily, efficacy was comparable to that in full-dose sorafenib trials, yet no patients required dose adjustments for toxicity or discontinued treatment due to adverse events.
In current clinical practice, full-dose sorafenib may be perceived as unsafe for patients with advanced DTC due to comorbidities and relative contraindications such as poor performance status, renal or hepatic dysfunction, high risk of bleeding or fistula formation, or extremes of age. In these cases, sorafenib is often started at doses <800 mg daily. To understand the effects of reduced sorafenib starting doses on treatment tolerability and efficacy, the research team examined real-world sorafenib practice patterns in 75 patients with metastatic DTC who were treated outside of a clinical trial at the MD Anderson Cancer Center between January 2005 and July 2013. Of these patients, 51 started with full-dose sorafenib (800 mg daily) and 24 started with doses <800 mg/day. In the reduced dose group, 23 patients started with 400 mg daily, while 1 patient started with 200 mg daily.
Results suggested that starting sorafenib at a reduced dose (<800 mg daily) did not adversely affect the efficacy of treatment. There were no statistically significant differences between full-dose and reduced-dose sorafenib with regard to any efficacy endpoints, including median time to progression (11 months vs. 8 months; p=0.354), time to treatment failure (10 months vs. 8 months; p=0.56), or overall survival (56 months vs. 30 months; p=0.08), although the authors theorize that the lack of statistical significance for overall survival may be due to the study’s small sample size.
In a surprising finding, however, when compared with sorafenib 800 mg daily, the lower starting dose of sorafenib was associated with similar high rates of dose reduction (59% vs. 43%), drug interruption (65% vs. 67%), and discontinuation due to toxicity (21% vs. 9%) or disease progression (79% vs. 91%).
Based on these findings, the study authors concluded that a lower dose of sorafenib (<800 mg daily) may be started in challenging cases of advanced DTC, when full-dose sorafenib is perceived to be unsafe. If treatment with sorafenib is tolerated, the starting dose may be subsequently increased to the standard full dose. The research team suggests that prospective studies are needed to determine the optimal approach to dose-titration and to assess the effect of cumulative sorafenib doses on clinical outcomes.
“It remains unclear why patients with DTC have higher toxicity rates in response to full-dose sorafenib as compared to patients with hepatocellular and renal cell carcinoma,” Dr. Dadu said. Future trials are needed to explore this observation as well, she added.
Herb Chen, MD, the chief of endocrine surgery at the University of Wisconsin and a member of The Oncologist’s editorial board said, “These experienced investigators have made an important observation regarding the dosing of sorafenib for patients with advanced thyroid cancer. While there is a trend towards a small difference in response rate between those starting on a lower dose versus a standard dose, it is likely that these patients benefitted from lower dose therapy. This is noteworthy as many patients cannot tolerate the standard dosing and thus this study provides the first evidence that using the lower dosing regimen may be an effective strategy to treat thyroid cancer patients."
The study will appear in the May issue of The Oncologist.
The full article, titled “Efficacy and Tolerability of Different Starting Doses of Sorafenib in Patients with Differentiated Thyroid Cancer,” can be accessed at http://www.TheOncologist.com.
About The Oncologist
Established by oncologists to help physicians better manage their practices in an ever-changing environment, The Oncologist® is the official journal of the Society for Translational Oncology (STO). Now in its 19th year, this internationally peer-reviewed journal focuses on clear and concise interpretation addressing the multimodality diagnosis, treatment, and quality of life of the cancer patient. Each issue is meant to impact the practice of oncology and to facilitate significant communication in the introduction of new medical treatments and technologies. For more information, visit http://www.TheOncologist.com.
About AlphaMed Press: Established in 1983, AlphaMed Press, with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes three internationally renowned peer-reviewed journals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines. STEM CELLS® (http://www.StemCells.com), which celebrates its 32nd year in 2014, is the world's first journal devoted to this fast paced field of research. THE ONCOLOGIST® (http://www.TheOncologist.com), entering its 19th year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. STEM CELLS TRANSLATIONAL MEDICINE® (http://www.StemCellsTM.com), in its third year, is dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices.