Teaching pack: Radiopharmaceuticals & Theranostics

Theranostic pairs (68Ga/18F for PET imaging; 177Lu for beta therapy; 225Ac/212Pb for alpha therapy) against PSMA, SSTR, FAP and more. Pluvicto and Lutathera are approved; alpha emitters and new targets are in late-stage trials. Isotope supply is the bottleneck.

• Alpha-emitter nanogenerators and daughter trapping: Actinium-225 releases four alpha particles as it decays, but the daughters escape and irradiate the kidneys and salivary glands. Nanocarriers try to hold them in place.
• Auger-electron therapy: Radioactive atoms that spray very short-range electrons, lethal only if the atom sits on or inside the cell's DNA.
• Medical cyclotrons, hot cells, and synthesis modules: The particle accelerators and shielded robotic chemistry boxes that make PET tracers in hospital basements and commercial pharmacies.
• MIBG imaging and 131I-MIBG therapy: A noradrenaline look-alike that neuroblastoma cells swallow: labelled with a small amount of radioactivity it shows the tumour on a scan; with a large amount it treats it.
• Peptide receptor radionuclide therapy (PRRT): A radioactive version of the hormone mimic used for the scan; it homes to neuroendocrine tumour cells and irradiates them from inside.
• PET tracer manufacturing and distribution: Making PSMA, FDG, and new tracers under drug-manufacturing rules and delivering them daily.
• PSMA PET: A prostate-cancer-specific PET scan that finds spread far earlier than CT or bone scan, and tells you whether a matched radioactive drug will work.
• Radio-antibody & radio-ADC: Attaching a radioactive atom to an antibody, so an ADC's targeting is used to deliver radiation instead of chemotherapy.
• Radioembolisation (TARE / SIRT, yttrium-90): Millions of tiny radioactive glass or resin beads are injected into the liver artery, lodging in the tumour and irradiating it from within.
• Radioiodine therapy and whole-body iodine scanning: Using the thyroid's natural appetite for iodine to image and treat thyroid cancer with a radioactive form of it. The oldest theranostic, and now used more selectively than it was.

• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Radioiodine and early radioimmunotherapy (historic)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Radium-223 and Lutathera (historic)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · PSMA theranostics (current)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Earlier lines, consolidation, and an M&A wave (current)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Alpha emitters and new targets (emerging)
• Radiopharmaceutical roadmap: iodine → lutetium → actinium · Speculative: radioligands as a standard modality (speculative)

• VISION (phase 3, n=831): Overall survival: 15.3 months vs 11.3 months, HR 0.62
• PSMAddition (phase 3, n=1,144): Radiographic progression-free survival: Updated HR 0.67; OS HR 0.80, immature
• ALSYMPCA (phase 3, n=921): Overall survival: 14.9 months vs 11.3 months, HR 0.7
• IoN (phase 3, n=504): Recurrence-free at 5 years: 98% vs 96%
• ESTIMABL2 (phase 3, n=776): Patients without events at 3 years: 95.6% vs 95.9%
• COMPETE (phase 3, n=309): Progression-free survival: 23.9 months vs 14.1 months, HR 0.67

1. What is theranostics and what is the best-known example?
   Answer

   Using the same targeting molecule for a diagnostic scan and a treatment: PSMA PET shows where prostate cancer is, and 177Lu-PSMA-617 (Pluvicto) delivers radiation to the same target.
2. What did the VISION trial show?
   Answer

   177Lu-PSMA-617 plus standard care improved overall survival (15.3 vs 11.3 months, HR 0.62) in PSMA-positive metastatic castration-resistant prostate cancer after ARPI and taxane.
3. Why might an alpha-emitting PSMA drug work after lutetium PSMA has stopped working?
   Answer

   Alpha particles (actinium-225) deposit far more energy over 50-100 µm, causing clustered double-strand breaks independent of oxygen and cell cycle, so beta-resistant, hypoxic, or small-volume disease can still be killed; retrospective series show PSA responses in about half after 177Lu failure. Supply of Ac-225 and salivary toxicity are the limits.
4. What is the difference between lutetium-177 and actinium-225 as therapeutic isotopes?
   Answer

   177Lu emits beta particles (range 1-10 mm, crossfire helps bulky heterogeneous tumours, marrow toxicity, 6.7-day half-life); 225Ac emits alpha particles (range 50-100 µm, very high energy, oxygen-independent clustered DNA damage, good for micrometastases, daughter redistribution and supply constraints).
5. Why is actinium-225 supply a problem?
   Answer

   It is made in tiny quantities from a legacy thorium-229 stockpile or accelerators; commercial-scale expansion is a 3-5 year effort (TerraPower's Philadelphia plant aims for a 20-fold increase), so phase 3 alpha trials and future launches are gated by production.