Medically induced euthyroid hypothyroxinemia may improve outcomes in glioblastoma (GBM) patients-an observational study
A.Hercbergs, Cleveland Clinic,Cleveland OH ,USA, D.Blumenthal ,Ichilov Medical Center ,Tel Aviv ,Israel
There is increasing documentation, but still limited general appreciation, of the proliferative effect of circulating L-thyroxine (L-T4)on solid tumors.
Clinical studies have shown that interventionallowering of serum free thyroxine (FT4) may be associated withextended survival in patients with some terminal cancers. Thyroxine [T4] is a growth factor that via a receptor on integrin avbeta3 of tumor cells and active endothelium activates mitogenesis , angiogenesis and tumor growth..
T4 is metabolically inactive but functionally is a pro-hormone for the metabolically active hormone triiodothyronine[T3] .
T3 is similarly mitogenic but only at significantly higher [10-100x] supra-physiological concentrations.
In earlier studies of 56 patients with recurrent high grade glioma treated with propylthiouracil 50% of whom became hypothyroid [ hypothyroxinemic ] survival was significantly prolonged but associated with morbidity.
Following reports that T3 in physiological concentrations is significantly less [10-100fold] less mitogenic than T4 , 3,3,5-triiodo-L-thyronine(L-T3) at 5-10 mcg twice daily concurrently with methimazole, 40-50 mg /day was used to suppress endogenousthyrotropin (TSH ] ,induce euthyroid hypothyroxinemia [HT]
RESULTS HT was achieved in 13 high grade GBM patients treated on a compassionate basis .All of 13 patients [100%] became hypothyroxinemic within 4-8 weeks without symptoms of clinical hypothyroidism. Median follow up time is 17 monthe [5-54 mo.] and 10/13 patients are alive at 12 -months.Median survival is 18 months.
One deteriorating patient improved performance status along with significant tumor regression .
CONCLUSION Exploiting the divergence between the
predominantly metabolic actions (with reduced oncogenic
potential) of T3 and the pro-oncogenic actions of T4.to induce euthyroid hypothyroxinemia is a novel , non-toxic and potentially effective approach in GBM management.Larger controlled studies are needed .