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

doi:10.1016/j.ejca.2020.04.023

European Journal of Cancer

Volume 133, July 2020, Pages 66-73

https://doi.org/10.1016/j.ejca.2020.04.023 Get rights and content

Highlights

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We identified free triiodothyronine (FT3)/free thyroxine (FT4) ratio as prognostic tool in colorectal cancer patients receiving regorafenib.
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The prognostic value of FT3/FT4 ratio was confirmed in the CORRECT trial.
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Any predictive role for FT3/FT4 ratio was ruled out.
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FT3/FT4 might be rapidly adopted as stratification factor in future clinical trials.
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Our results pave the way for studies on therapeutic implications for thyroid hormones.

Abstract

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.

Introduction

Thanks to the introduction of new specific targeted treatments and strategies, outcome of patients with advanced metastatic colorectal cancer (mCRC) has progressively improved; however, prognosis for the majority of patients remains poor [[1], [2], [3]]. Prognostic clinical and molecular features such as physical performance status, baseline serum lactate dehydrogenase (LDH) levels, burden of cancer disease, previous lines of treatment, microsatellite instability and BRAF/RAS mutations have been identified [4]. Nonetheless, better tools for guiding patient selection and clinical decision making are needed, especially in later lines of treatment.

Our group recently showed that the peripheral thyroid hormone ratio (free triiodothyronine [FT3]/free thyroxine [FT4]) predicts, independently from other validated prognostic factors, overall survival (OS) and progression-free survival (PFS) in mCRC patients treated with regorafenib [5]. Because the peripheral activity of thyroid hormones depends on the FT3/FT4 ratio, we hypothesised that being it regulated by deiodinase I and II, the activity of those enzymes is modulated as metabolic response to cancer burden [6].

Some studies in the past years have documented a significant prognostic role of changes in thyroid hormone levels, especially FT3, in several clinical conditions. Indeed, in patients with acute diseases or advanced cancer, low FT3 levels predicted a worse clinical outcome, whereas in progressing hepatocellular carcinoma patients, high FT4 levels were associated with shorter survival [[7], [8], [9]]. Moreover, a recent study in hospitalised elderly patients with acute diseases showed that peripheral thyroid hormone conversion impairment, as assessed by FT3/FT4 ratio, tightly correlates with frail status and survival even in patients with free thyroid hormones within the reference range [10]. Given that the ratio of FT3/FT4 in advanced CRC patients and in patients hospitalised for acute diseases and without low-T3 syndrome outperforms each thyroid hormone (FT3, FT4) in predicting survival, we hypothesised that peripheral FT4 deiodination may be an early and crucial key point of systemic response to acute/systemic diseases.

Owing to the strong biologic rationale and to the consistency of our previous data, we planned the present post hoc analysis of the CORRECT trial [11], which proved the efficacy of regorafenib versus placebo in mCRC patients to (a) investigate the possible predictive value of the FT3/FT4 ratio to regorafenib and (b) validate the prognostic role of FT3/FT4 ratio in chemorefractory patients.

Section snippets

Materials and methods

Patients data were retrospectively extracted from the phase III placebo-controlled clinical trial CORRECT [10]. The study involved 114 centres in 16 countries in North America, Europe, Asia and Australia and investigated regorafenib efficacy in patients with histological or cytological documentation of adenocarcinoma of the colon or rectum who received locally and currently approved standard therapies and had disease progression during or within 3 months after the last administration of the

Statistical methods

The main objectives of this analysis were to determine a possible predictive role of the FT3/FT4 ratio in patients treated with regorafenib compared with placebo and to evaluate the prognostic value in terms of OS and PFS of FT3/FT4 ratio in mCRC patients receiving regorafenib. Patients from each randomisation arm were grouped according to FT3/FT4 ratio tertile values, according to our previous experience—T1 (low), T2 (intermediate) and T3 (high). Primary end-point was the impact of FT3/FT4

Results

Our analysis population included 758 out of the 760 randomised patients (503 randomised to regorafenib and 255 to placebo). Patients demographic data and principal clinical characteristics are reported in Table 1. Clinical features were well balanced among regorafenib and placebo group and in line with those observed in the intent-to-treat CORRECT study population.

Results of univariate Cox regression analysis for OS of both study arms are reported in Table 2.

In patients randomised to

Discussion

The present study clearly demonstrates the impact of peripheral thyroid hormone metabolism in tumour progression and survival of advanced CRC patients either treated or not with the multikinase inhibitor regorafenib.

Moving from our previous retrospective experience [5], we designed the present analysis to validate our results in a randomised phase III clinical trial including a large data set of patients and centralised laboratory tests. Consistently with the primary hypothesis, the prognostic

Grant support

None.

Conflict of interest statement

Emmanuelle Dochy is an employee of Bayer. No other relevant relationship to disclose.

Acknowledgements

The authors thank Kumari Chandrawansa for the statistical support.

References (23)

C. Cremolini et al.
FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study
Lancet Oncol
(2015)
V. Heinemann et al.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial
Lancet Oncol
(2014)
M. Schirripa et al.
Prognostic value of thyroid hormone ratios in patients with advanced metastatic colorectal cancer treated with regorafenib: the TOREADOR study
Clin Colorectal Canc
(2018)
A. Grothey et al.
Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial
Lancet
(2013)
F. Pietrantonio et al.
Estimating 12-week death probability in patients with refractory metastatic colorectal cancer: the Colon Life nomogram
Ann Oncol
(2017)
F. Loupakis et al.
A validated prognostic classifier for (V600E)BRAF-mutated metastatic colorectal cancer: the 'BRAF BeCool' study
Eur J Canc
(2019)
M. Dentice et al.
beta-Catenin regulates deiodinase levels and thyroid hormone signaling in colon cancer cells
Gastroenterology
(2012)
S.M. Adler et al.
The nonthyroidal illness syndrome
Endocrinol Metab Clin N Am
(2007)
M.G. Fakih
Metastatic colorectal cancer: current state and future directions
J Clin Oncol
(2015)
M. Schirripa et al.
Biomarker in colorectal cancer
Cancer J
(2016)

A.L. Maia et al.

Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans

J Clin Invest

(2005)

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¹: Marta Schirripa and Giuseppe Pasqualetti equally contributed as first author.

²: Fabio Monzani and Fotios Loupakis equally contributed as senior author.

View full text

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

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Statistical methods

Results

Discussion

Grant support

Conflict of interest statement

Acknowledgements

Lancet Oncol

Lancet Oncol

Clin Colorectal Canc

Lancet

Ann Oncol

Eur J Canc

Gastroenterology

Endocrinol Metab Clin N Am

Metastatic colorectal cancer: current state and future directions

J Clin Oncol

Biomarker in colorectal cancer

Cancer J

Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans

J Clin Invest

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