Thyroid hormones ratio is a major prognostic marker in advanced metastatic colorectal cancer: Results from the phase III randomised CORRECT trial

Background: Free triiodothyronine (FT3)/free thyroxine (FT4) ratio is an index estimating the peripheral activity of thyroid hormones. In a previous experience, we identified a prognostic role for FT3/FT4 ratio in chemorefractory patients treated with regorafenib. Therefore, we planned this post hoc analysis of the phase III CORRECT trial of regorafenib versus placebo. Methods: Seven hundred fifty-eight out of 760 randomised patients (503 in the regorafenib and 255 in the placebo arm) were evaluable for the present analyses, based on availability of FT3 and FT4 baseline values. Co-primary objectives were to explore the predictive role of FT3/FT4 ratio in patients treated with regorafenib compared with placebo and to validate the prognostic value of FT3/FT4 ratio in the CORRECT trial. Results: For patients randomised to regorafenib, median overall survival (OS) was 4.0, 7.5 and 9.8 months in low, intermediate and high FT3/FT4 ratio subgroups, respectively. Hazard ratio (HR) for OS was 0.40 (p < 0.0001) when comparing intermediate versus low and 0.32 (p < 0.0001) when comparing high versus low FT3/FT4 ratio. In the placebo arm, median OS was 3.3, 5.6 and 7.7 months, in the three subgroups. HR for OS was 0.47 (p < 0.0001) when comparing intermediate versus low and 0.33 (p < 0.0001) when comparing high versus low. FT3/FT4 ratio retained its association with OS in the multivariate model in both arms. Conclusions: While rejecting the predictive effect of baseline FT3/FT4 ratio, present data strengthen the prognostic role of the ratio, pave the way for direct clinical application, underline the need for a better biological understanding and suggest possible therapeutic implications for thyroid hormones.