Avidity-guided radionuclide therapy for thyroid cancer

Abstract

The treatment of differentiated thyroid cancer has three main modalities: surgery, hormone suppression and radioiodine therapy. Effective radioiodine therapy requires cancer cells to be iodine avid, i.e. exhibit relatively functional iodine transport and retention. The iodine avidity is often unknown at the time of initial treatment and the range has not been quantified in detail.

To find the true range of iodine avidity in papillary and poorly differentiated thyroid cancer, a unique prospective study was designed. Tissue samples were collected directly after surgery in order to estimate iodine concentrations following a preoperative injection of radioactive iodine. Clinical, molecular and genetic parameters were studied in relation to the iodine avidity observed in the tissue samples. Furthermore, computer modelling using Monte Carlo simulations was performed to establish the impact of target geometry and size.

The results show that iodine avidity was correlated to the proportion of tumour cells that express thyroglobulin (correlation coefficient r = 0.50) and the tumoural Ki-67 index (r = -0.49). Avidity was found to be seven-fold higher in favourable histological subtypes of PTC. High patient age was also found significantly correlated with low iodine avidity (r = -0.35). No strong connection between avidity and tumour size or TNM staging was found, despite TNM being the current main guiding parameter in radioiodine treatment strategy selection. Furthermore, links between low iodine avidity and mutations in BRAF (18-fold lower avidity) and the TERT promoter (10- fold lower avidity) were found, if mutations were observed in lymph node metastases. Expression of the iodine-transporter NIS was found to indicate high iodine avidity (40-fold higher avidity), but only when localised at the plasma membrane, which appears to be rare in thyroid cancer cells.

Follow-up studies showed that the iodine avidity estimated in primary tumours and lymph node metastases at initial surgery predicted uptake in persistent metastases well (both regional and distant metastases). This confirms that knowledge gathered from the initial surgical specimens can reliably help guide treatment targeting subsequent metastases.

The Monte Carlo simulations showed that for small targets, both size and shape of the target tissue has an impact on radioiodine therapy, with up to a three-fold lower effectiveness for compressed targets at the size-threshold for micrometastases. However, the effect was dwarfed by the much larger variation in iodine avidity observed in the prospective material.

Data from this work has strengthened the link between iodine avidity and many readily available parameters, that can guide treatment. A shift to avidity-guided therapy for high-risk patients is proposed to better adapt the radioiodine strategy to expected effect than was previously possible.