Letter to the Editor: Radioiodine Is Molecular Radiotherapy Governed by Predictable Deterministic Radiobiology Expressed in Gray,Not Millicuries

Dear Editor:

Systemic radionuclide therapy such as radioiodine (¹³¹I) have much to learn from the rapid scientific progress of radioembolization, which is now clinically implementing voxel-based theranostics (1). The core principle driving radioembolization's success is its recognition that internal radionuclide therapy is fundamentally a form of low dose rate radiotherapy governed by biophysical laws with predictable dose(Gy)-response effects (1,2). Recently, Simões-Pereira et al. suggested clinical equivalence between thyroid hormone withdrawal (THW) versus recombinant human thyroid stimulating hormone (rhTSH) for radioiodine therapy in metastatic differentiated thyroid cancer (3). However, their lack of tumor dosimetry confounds their results (2).

Without additional effort to calculate tumor absorbed doses (Gy), patients cannot be appropriately stratified for meaningful outcomes analysis (1,2). This is because the critical parameter in radioiodine therapy is the absorbed dose expressed in gray (Gy), not activity expressed in Curie (Ci) or Bequerel (Bq). In the study by Simões-Pereira et al., their patients were empirically treated with only 100–150 mCi (3.7–5.55 GBq) of radioiodine per fraction, which is generally inadequate for metastases (3). Therefore, the alternate explanation for their lack of statistically significant outcome differences between THW versus rhTSH was simply because both groups were undertreated. Interestingly, their results may suggest a trend toward THW being more beneficial to outcomes than rhTSH, although this did not reach statistical significance (3).

Depending on lesional parameters and kinetics, 1 mCi (37 MBq) of radioiodine may result in tumor absorbed doses ranging from <1 Gy to >100 Gy. Explained by the EANM Therapy Committee, the mean absorbed dose of iodine-avid tissue, D ( G y ) is (4): D = A ⋅ Ē ⋅ τ M ,

where A ( M B q ) is administered activity, Ē is mean energy deposited per decay of radioiodine that varies with tissue size and geometry, M is target tissue mass (g), and τ ( d a y ) is the time integral of fractional uptake in target tissue, now known as Time Integrated Activity Coefficient, formerly known as Residence Time.

Parameters Ē and M are inherent to the metastases and beyond our control. However, we have control over A and τ to optimize the chances of achieving the minimum tumor absorbed dose threshold of 80 Gy. In other words, parameters A and τ are modifiable dosimetric parameters that we must fully exploit to optimize each radioiodine therapy.

By rendering tissues hypothyroid in conjunction with endogenous TSH increase and a more effective low iodine diet by omission of iodine from thyroxine, THW increases τ to improve the tumor absorbed dose more than rhTSH (5). τ by rhTSH increases less than THW, a missed opportunity (5). This is why THW is the preferred preparation method for metastases. THW may be substituted by rhTSH only where iatrogenic hypothyroidism is expected to be medically, psychologically, or socially detrimental.

As a low-grade malignancy, metastatic differentiated thyroid cancer has forgiven our sins for decades and, by its indolent nature, shall continue to forgive us. However, patients with widespread metastases where prognosis is less than a decade deserve better. Radioiodine should not be prescribed or analyzed like a common medicine. Yes, the Holy Gray exists. Learn from modern radioembolization (1).