1. Define radio-theranostics and how it can contribute to precision medicine.
2. Provide several examples of radio-theranostics in various clinical settings.
3. Describe advantages and limitations of radio-theranostics.
absorption and energy transfer, and very long path lengths, resulting in lower radiation to the target and increased but low-level energy radiation to surrounding tissue (emitted for example by 123I). Beta particles on the other hand (emitted for example by 131I, 177Lu, and 90Y) have higher energy transfer to the target (0.2-2 keV/µm) at path lengths that can be up to 11 mm (Table 16.1). Alpha particles (emitted for example by 223Ra) have very high energy transfer (80 keV/µm) and very short path lengths (<100 µm), which are usually the diameter of a few cells. Beta emitters have been proposed for large-/mid-size metastases for the reasons discussed earlier, whereas alpha emitters are considered more advantageous in non-solid tumors and micrometastases. Auger electron emitters (emitted for example by 111In) can be used for therapy as well, although Auger electrons are generally less effective due to very short path length (2-500 nm) and low energy deposition (4-26 keV/mm), and the radionuclide usually needs to be intra-cellular to be effective. Having said all that, rarely a radionuclide has a single type of emission. Most of them have a combination of two or more types of emissions with different abundancies. This property actually makes some of these radionuclides amenable, although not ideal, for both diagnostic and therapeutic purposes. For instance, some beta emitters used for therapy also emit gamma photons and can be used to confirm the molecular targeting after therapy or even dosimetry (e.g., 131I and 177Lu).
Table 16.1 RADIONUCLIDES OF POSSIBLE USE IN THERAPEUTIC THERANOSTICS
“strict” definition of radio-theranostics does not encompass these compounds, they definitely seem to work “functionally” as a theranostic tandem or what could be called a “pseudo-theranostic” pair.
duodenum, or pancreas. As a fraction of microspheres enters systemic circulation through these arteriovenous shunts and blood supply of adjacent organs, they may cause pneumonitis, cholecystitis, gastritis, duodenitis, and pancreatitis. A radiation dose of 30 Gy (or a cumulative dose of 50 Gy) to the lung is associated with pneumonitis, and long-term significant morbidity due to eventual development of pulmonary fibrosis. Therefore, prior to intra-arterial radioembolization of liver lesions, the hepatic arterial anatomy has to be mapped with catheter angiography and collaterals to other organs visualized, so that they can be coiled. The degree of hepatopulmonary shunting from the macro and microcirculation also has to be mapped and quantitated prior to hepatic arterial embolization via intra-arterial administration of 99mTc-macro aggregated albumin (MAA) and subsequent imaging. The administered radioactivity by means of microspheres may need to be limited if there is significant shunting to the lungs or if there is any activity in other abdominopelvic viscera that cannot be corrected by coil embolization. In that sense, this practice works in tandem with a diagnostic image that guides the therapeutic component. Although not molecularly targeted or using the same molecular probe for diagnostic and therapeutic purposes, the utility of this combination of diagnostic/therapeutic pair is necessary, used in this case more to avoid undesirable and preventable side effects than to assess the effectiveness of the therapy. In that sense, intra-arterial MAA is a surrogate for microspheres.
Table 16.2 COMMONLY USED IODINE ISOTOPES IN THERANOSTICS
Differentiated thyroid cancer which includes papillary and follicular histology is a common malignancy and has a favorable prognosis and very low mortality compared with most other malignancies. Differentiated thyroid cancer (papillary thyroid carcinoma being the most common comprising 70%-75% of differentiated thyroid carcinomas, followed by follicular thyroid carcinoma in 10%-15% of cases in the United States and 17%-20% in the world) expresses NIS. Hurthle cell carcinoma is an aggressive variant of follicular carcinoma and is associated with low avidity for radioiodine in most patients (21). In general, NIS expression is lower in cancer than in normal thyroid follicular cells and may be even lower in metastatic lesions than in the primary cancer tissue. Therefore, stimulation of TSH release in patients with history of thyroid cancer and total thyroidectomy via withdrawal of thyroid hormone intake, or intramuscular administration of recombinant human TSH (rhTSH, thyrotropin) is used to increase radioiodine uptake in residual/recurrent/metastatic thyroid cancer for diagnostic (123I and 124I) and therapeutic purposes (131I) using theranostic pairs of the iodine family. Poorly differentiated and dedifferentiated thyroid cancer have reduced functional NIS expression at the cellular membrane and loses the ability to trap Iodine. Therefore, the utility of theranostics with radioiodine pairs also decreases. Nevertheless, some medications such as selumetinib are now known to induce re-differentiation of these cancer cells and increase radioiodine uptake again (22). The clinical utility of these medications prior to 124I/131I diagnostic/treatment is being evaluated (23) and already used currently in some Institutions (Fig. 16.1).