Redifferentiation Therapy with Retinoids: Therapeutic Option for Advanced Follicular and Papillary Thyroid Carcinoma

Abstract

During the course of tumor progression the differentiated morphologic and functional characteristics of differentiated thyroid carcinomas (DTC) disappear. This corresponds to more aggressive growth, metastatic spread, and loss of iodine uptake. Experimental data give strong evidence that differentiated functions of iodine metabolism can be reinduced by retinoic acids. Results of a study performed in patients with advanced DTC are presented. Twenty patients with DTC (eight follicular, seven papillary, five oxyphilic) were selected for treatment with retinoic acid 1.5 mg/kg body weight/day over 5 weeks. All patients had advanced tumor stages with prior operative and radioiodine treatment. Extensive tumor invasion, distant metastatic spread, or insufficient or no radioiodine uptake precluded any conventional therapeutic option. The aim was to assess the changes under retinoid treatment. Iodine uptake increased in eight patients (three follicular, three papillary, two oxyphilic). Thyroglobulin (TG) as parameter for tumor mass and differentiation increased in 12 (63%) patients, decreased in 6 (32%), and did not change in 1 (5%). Retinoids do have an effect on differentiation status of DTC, reinducing iodine uptake in 50% of patients. TG levels do not always parallel a response in iodine uptake.

Retinoic acid induces sodium/iodide symporter gene expression and radioiodide uptake in the MCF-7 breast cancer cell line

“…Thyroid cancer requires high levels of TSH to induce or to maximally stimulate 131 I uptake (1). In some differentiated thyroid cancer, treatment with retinoic acid (RA), in addition to TSH stimulation, has been reported to induce NIS mRNA expression (9) and NIS activity (10). The results of clinical pilot studies have suggested that iodide uptake may be stimulated by RA treatment into metastases of thyroid cancer that do not take up 131 I under standard treatment conditions (10).…”

Alternative Medical Treatment for Radioiodine-Refractory Thyroid Cancers

“…In the first clinical trial for RA, Simon et al described an increase in RI uptake of thyroid cancer cells in 40% (4/10) of patients [9]. Likewise, other initial clinical trials also reported that about 40-50% of RI-refractory patients showed an increase in RI uptake [10][11][12]. However, the following clinical trials reported much lower rates of RI uptake increase.…”

Innovative strategies for the treatment of thyroid cancer

“…They have prompted a multicentric clinical study to test the potential of retinoids for a redifferentiation therapy of thyroid cancer. So far, 75 patients with poorly differentiated, inoperable thyroid cancer and absent or insuf®cient iodide uptake have been included (69,70). They were treated with oral doses of 1.0±1.5 mg 13-cis-RA per kg body weight and day.…”