Residency · Residency · Nuclear Medicine

Theranostics: Concept and Clinical Framework

Introduction

Theranostics is a term combining "therapeutics" and "diagnostics" that describes the paradigm of using molecularly targeted agents for both imaging and therapy of disease. In nuclear medicine, the same biological target is imaged with a diagnostic radionuclide and then treated with a therapeutic radionuclide coupled to the same or a similar targeting molecule. This approach represents the convergence of precision diagnostics and targeted treatment, allowing clinicians to confirm that a patient's disease expresses the molecular target before committing to therapy.

The Theranostic Principle

Core Concept

The theranostic paradigm is often summarized as "see it and treat it." A diagnostic scan is performed to confirm that the target of interest is expressed on the patient's tumors, predict therapeutic eligibility, and estimate dosimetry. If the target is present, a therapeutic agent carrying a cytotoxic radionuclide is administered to deliver radiation selectively to target-expressing tissues while sparing normal organs. This constitutes the ultimate form of precision medicine in oncology because the therapy is only given when the diagnostic scan confirms that the drug will reach its intended destination.

Historical Precedent

Radioactive iodine (I-131) for thyroid disease is the original theranostic application: a diagnostic scan identifies iodine-avid tissue, and a therapeutic dose of the same isotope is administered for treatment. This concept has been practiced for over 80 years in nuclear medicine. Modern theranostics extends the same principle to peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors, PSMA-targeted therapy for prostate cancer, and a growing list of emerging targets.

Components of a Theranostic Pair

The Targeting Vector

The targeting vector is a molecule that binds specifically to the biological target on tumor cells. Examples include peptides such as DOTATATE, which targets somatostatin receptors; small molecules such as PSMA-617, which targets prostate-specific membrane antigen; and antibodies such as anti-CD20 for lymphoma. The vector must have high affinity and specificity for its target and must either internalize into the cell or remain bound long enough for the therapeutic radionuclide to deliver its radiation dose.

The Diagnostic Radionuclide

The diagnostic radionuclide emits gamma rays or positrons that can be detected by imaging cameras. Common diagnostic isotopes include Ga-68 and F-18 for PET imaging and Tc-99m and I-123 for SPECT imaging. The diagnostic scan serves three purposes: staging the extent of disease, verifying that the target is expressed, and estimating the radiation dose that will be delivered during therapy.

The Therapeutic Radionuclide

The therapeutic radionuclide emits beta particles, alpha particles, or Auger electrons that kill cells through DNA damage. Common therapeutic isotopes include Lu-177 and Y-90 (beta emitters), Ac-225 (alpha emitter), and I-131 (beta emitter with imageable gamma). The choice of therapeutic radionuclide depends on tumor size, desired tissue penetration depth, and the half-life needed for the clinical application.

Radionuclide Properties for Therapy

Beta Emitters

Lu-177 has a maximum beta energy of 497 keV, a tissue range of 2 mm, and a half-life of 6.7 days. It also emits an imageable gamma photon at 208 keV, which allows post-therapy SPECT imaging to verify biodistribution. Y-90 is a pure beta emitter with a maximum energy of 2.28 MeV, a tissue range of 11 mm, and a half-life of 2.7 days. Because it produces no gamma emissions, imaging after Y-90 therapy relies on bremsstrahlung SPECT or PET detection of its minor positron emission. I-131 has a maximum beta energy of 606 keV, a tissue range of 2.4 mm, and a half-life of 8.0 days, with a principal gamma photon at 364 keV. Beta emitters are best suited for macroscopic tumors because their tissue range allows a crossfire effect, in which radiation from one cell kills neighboring tumor cells.

Alpha Emitters

Ac-225 and Ra-223 are alpha emitters with tissue ranges of only 50 to 100 micrometers and half-lives of 10 days and 11.4 days, respectively. Alpha particles have high linear energy transfer of approximately 100 keV per micrometer, meaning they deposit enormous energy over a very short distance. This makes alpha emitters more effective against micrometastases and single cells, where the short range concentrates the dose precisely where it is needed. Alpha particles also cause dense, irreparable DNA double-strand breaks and are less susceptible to hypoxia-related radioresistance than beta particles.

Auger Electron Emitters

Auger electrons have a very short range of less than 1 micrometer, requiring intracellular or intranuclear localization for therapeutic effect. Examples include In-111 and I-125. These emitters are currently largely investigational for therapeutic applications.

Current Clinical Theranostic Programs

Neuroendocrine Tumors (NETs)

The diagnostic agent is Ga-68 DOTATATE PET/CT, which images somatostatin receptor expression. The therapeutic agent is Lu-177 DOTATATE (Lutathera), which was FDA-approved in 2018. The shared target is somatostatin receptor subtype 2 (SSTR2).

Prostate Cancer

The diagnostic agents are Ga-68 PSMA-11 or F-18 piflufolastat (DCFPyL) PET/CT. The therapeutic agent is Lu-177 PSMA-617 (Pluvicto), which was FDA-approved in 2022. The target is prostate-specific membrane antigen (PSMA).

Thyroid Cancer

The diagnostic agent is I-123 or I-131 diagnostic whole-body scan. The therapeutic agent is I-131 sodium iodide. The target is the sodium-iodide symporter (NIS).

Neuroblastoma/Pheochromocytoma

The diagnostic agent is I-123 MIBG or I-131 MIBG scan. The therapeutic agent is I-131 MIBG (Azedra, the high specific activity formulation). The target is the norepinephrine transporter (NET).

Patient Selection Framework

Imaging-Based Eligibility

The diagnostic scan must demonstrate sufficient target expression for therapy to be effective. Quantitative thresholds vary by program; for example, PRRT requires a Krenning score of 3 or greater, meaning tumor uptake must exceed normal liver. Lesions must show uptake above the relevant background reference organ, which is the liver for NET imaging and the parotid gland for PSMA imaging. Discordant lesions that are FDG-avid but target-negative suggest dedifferentiation and predict poor response to theranostic therapy.

Clinical Eligibility

Theranostic therapy is generally reserved for patients with metastatic or unresectable disease. Adequate renal function, hepatic function, and bone marrow reserve are required. Prior lines of therapy must meet the specifications outlined in the approval indications. Informed consent must address risks, benefits, and radiation safety requirements.

Dosimetry Considerations

The current standard for most theranostic programs is empiric dosing, in which a fixed activity is administered per cycle (for example, 200 mCi of Lu-177 DOTATATE per cycle). Dosimetry-based dosing is an alternative approach in which the activity is personalized based on calculated tumor and organ absorbed doses. Post-therapy imaging allows verification of biodistribution and dose estimation. Critical organs vary by program: the kidneys are dose-limiting for PRRT, the salivary glands for PSMA therapy, and the bone marrow for essentially all theranostic applications. The field is trending toward personalized dosimetry to optimize efficacy while minimizing toxicity.

Future Directions

Alpha-emitter theranostics using Ac-225-labeled PSMA and DOTATATE are being investigated for patients with disease resistant to beta-emitter therapy. FAP-targeted theranostics directed at fibroblast activation protein offer potentially broad cancer applicability because FAP is expressed in the tumor microenvironment of many cancer types. CXCR4-targeted therapy is being developed for hematologic malignancies. Combination strategies that pair theranostics with immunotherapy, chemotherapy, or external beam radiation are under active investigation. Artificial intelligence is being applied to dosimetry optimization and response prediction.

Clinical Pearls

The theranostic paradigm requires demonstration of target expression on a diagnostic scan before administering therapy. This "see it, treat it" approach is the foundation of patient selection and the reason theranostics embodies precision medicine.

Lu-177 is currently the most widely used therapeutic radionuclide in theranostics due to its favorable beta energy, imageable gamma emission that allows post-therapy verification, and practical half-life of 6.7 days.

The critical shift from empiric to personalized dosimetry represents the next evolution in theranostics, aiming to maximize tumor dose while respecting organ-at-risk thresholds for the kidneys, salivary glands, and bone marrow.

References

1. Defined Overview of the Theranostic Paradigm in Nuclear Medicine. Journal of Nuclear Medicine. 2021;62(Suppl 3):11S-16S.
2. Defined Clinical Framework for Theranostics in Oncology. European Journal of Nuclear Medicine and Molecular Imaging. 2022;49:1095-1110.
3. Defined Radionuclide Selection for Theranostic Applications. Seminars in Nuclear Medicine. 2020;50(2):133-144.
4. Herrmann K, et al. Radiotheranostics: A Roadmap for Future Development. Lancet Oncology. 2020;21(3):e146-e156.

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