Thyroid hormone ratio and clinical outcome: results from the Toreador Study

From a physiopathological point of view patients with advanced solid cancer and neoplastic cachexia might be associated, in some way, with frail older patients, a well-known and extensively described multi-factorial clinical condition, characterized by increased catabolism and marked muscle wasting. Interestingly, some studies documented a possible association between peripheral thyroid hormone levels and physical performance and/or survival of older patients, especially those with frailty. In details, higher levels of FT4 may predict poor outcome of older patients while, higher FT3 levels may be inversely related to better physical performance.

Overall survival of metastatic colon rectal cancer patients. Atlas of science

Fig. 1. Overall survival of metastatic colon rectal cancer patients according to FT3/FT4 tertiles (Modified from Schirripa et al. Clinical Colorectal Cancer 2018).

Given that both FT3 and FT4 peripheral concentration may, at least partially, depend on peripheral thyroxin deiodination, catalysed by deiodinase enzymes (isozyme D1, D2, and D3), some authors suggested that the FT3/FT4 ratio may reflect the complex metabolic alterations observed in specific clinical settings such as those related to frailty. In this regard, a previous study in hospitalized geriatric patients showed a significantly shorter survival in patients with the lowest quartile of FT3/FT4 ratio. Thus, the rationale of our work relied on the similarity between this clinical condition (frail syndrome), characterized by extreme muscle wasting (sarcopenia), and neoplastic cachexia. On this basis, we tried to document the potential predicting value of FT3/FT4 ratio in cachectic cancer patients.

We selected a retrospective cohort of patients (n=68) affected by advanced mCRC (stage IV) who underwent regorafenib treatment. Our results were subsequently challenged by means of a robust multivariate model which included many factors already known as prognostic in this setting. The population was chosen for the homogeneity of the oncologic disease and for the availability of basal thyroid function data (FT3, FT4, TSH) given the thyroid toxicity of regorafenib. Our results were strengthened by an external confirmation on an independent pool of patients (n=73) from another Italian Cancer Centre.

In our study, as well as in sarcopenic older patients, the FT3/FT4 ratio independently predicted patient survival and outperformed the measurement of the single free hormone (FT3 or FT4) or TSH in predicting mortality. In particulars, mCRC patients with the lowest tertile of the FT3/FT4 ratio presented a significant worse prognosis in term of overall survival (Fig. 1) and progression free survival.

In this experience, we only documented an association between FT3/FT4 ratio and survival in mCRC patients without analyzing possible bio-molecular mechanisms. Interestingly, many authors suggested that FT4 peripheral conversion is mainly carried out by D1 in the liver. At the same time, some evidences highlighted the role of D2, which is mostly expressed in muscle cells. In our study, we cannot rule out that both processes are involved given that many of our patients presented either an extensive liver involvement or clinical cachexia with reduced overall muscle mass. In conclusion, we identified FT3/FT4 ratio as a new prognostic factor in advanced mCRC patients receiving regorafenib. Specific studies are warranted to clarify the biological mechanisms of our findings in order to open the possibility for therapeutic targeting of FT3/FT4 ratio.

Giuseppe Pasqualetti, Fabio Monzani
Geriatrics Unit, Department of Clinicxal & Experimental Medicine, University of Pisa, Italy


Prognostic Value of Thyroid Hormone Ratios in Patients With Advanced Metastatic Colorectal Cancer Treated With Regorafenib: The TOREADOR Study.
Marta Schirripa, Giuseppe Pasqualetti, Riccardo Giampieri, Mario Scartozzi, Sara Lonardi, Laura Rumanò, Francesca Bergamo, Silvia Stragliotto, Sabina Murgioni, Giulia Alberti, Mario Domenico Rizzato, Alessandra Anna Prete, Marco Puzzoni, Valeria Pusceddu, Pina Ziranu, Fabiana Pani, Stefano Mariotti, Vittorina Zagonel, Fabio Monzani, Fotios Loupakis
Clin Colorectal Cancer. 2018 Sep


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