Summary (10 sec read)
Lutetium-177 (Lu-177), Actinium-225 (Ac-225), and Terbium-161 (Tb-161) are advanced *radioligand therapies targeting PSMA for treating metastatic castration-resistant prostate cancer (mCRPC). Lu-177 emits beta particles, making it effective for larger tumors, while Ac-225 emits alpha particles, delivering highly localized, potent radiation but with higher toxicity. Tb-161, an emerging alternative, combines beta particles with Auger electrons, potentially increasing efficacy while reducing side e
Prostate cancer treatment has evolved significantly with the introduction of targeted radionuclide therapy, which delivers radiation precisely to cancerous cells while minimizing damage to healthy tissues. Among the most promising approaches are Lutetium-177 (Lu-177), Actinium-225 (Ac-225), and the emerging Terbium-161 (Tb-161) therapies, all of which target the prostate-specific membrane antigen (PSMA). While Lu-177 and Ac-225 have already demonstrated clinical efficacy, Tb-161 is a promising newcomer with the potential to enhance treatment outcomes.
Efficacy and Mechanism of Action
Lu-177 Therapy: Lu-177 emits beta particles, which have a penetration range of up to 2 mm, making them suitable for targeting larger tumors. While effective, beta particles mainly cause single-strand DNA breaks, which some cancer cells can repair. Clinical trials show that Lu-177–PSMA therapy leads to a ≥50% decline in PSA levels in approximately 49% of patients ([https://pubmed.ncbi.nlm.nih.gov/39327114])
Ac-225 Therapy: Ac-225 emits alpha particles, which have significantly higher energy but a much shorter range (50-100 micrometers). This results in highly localized, double-strand DNA breaks, which are far more difficult for cancer cells to repair. Studies indicate that Ac-225–PSMA therapy achieves a ≥50% PSA decline in about 60% of patients, making it more effective than Lu-177, especially for radiation-resistant tumors
[(https://pubmed.ncbi.nlm.nih.gov/39327114/)). However, its high toxicity has limited its widespread use.
Tb-161 Therapy: Terbium-161 is an emerging radionuclide that emits beta particles like Lu-177 but also produces Auger electrons, which deliver a high-energy impact over a very short range. This unique property allows Tb-161 to achieve higher radiation dose deposition within tumor cells while sparing surrounding healthy tissues. Preclinical studies suggest that Tb-161 may be superior to Lu-177 in tumor cell destruction, though clinical validation is still underway.
Toxicity and Side Effects
While all three therapies aim to minimize systemic toxicity, their side effect profiles vary:
- Lu-177 Therapy: Common side effects include fatigue, mild nausea, and dry mouth (xerostomia). Mild bone marrow suppression can occur, and beta particles’ longer range slightly increases the risk of off-target radiation exposure to organs such as the kidneys.
- Ac-225 Therapy: The most notable drawback of Ac-225 therapy is severe xerostomia, as it delivers high radiation doses to PSMA-expressing salivary glands. Bone marrow suppression is also more pronounced, necessitating careful monitoring
(https://pubmed.ncbi.nlm.nih.gov/39552586/)).
Tb-161 Therapy: Due to its emission of short-range Auger electrons, Tb-161 may potentially reduce side effects by delivering highly localized radiation. However, further clinical studies are needed to confirm its safety profile.
Current and Future Clinical Applications
Lu-177 therapy is currently the most widely approved and used among the three, demonstrating improved progression-free survival and quality of life in patients with advanced mCRPC. It is often the first-line radioligand therapy.
Ac-225 therapy is emerging as a potent alternative, particularly for patients who do not respond to Lu-177. Despite its higher toxicity, its ability to overcome radiation resistance makes it a valuable option in aggressive prostate cancer cases.
Tb-161 therapy is still in early research stages, but its combination of beta and Auger electron emissions suggests that it may improve efficacy while reducing toxicity. If ongoing clinical trials confirm its benefits, it may become a future standard for precision radioligand therapy.
Lu-177, Ac-225, and Tb-161 represent the forefront of nuclear medicine therapy for prostate cancer. While Lu-177 is currently the most accessible and well-established, Ac-225 shows promise for aggressive, treatment-resistant cases, and Tb-161 offers a novel approach with potentially fewer side effects. The future of prostate cancer treatment is likely to involve personalized radionuclide therapy, using combinations or tailored approaches based on disease stage and patient response.
With continuous advancements in nuclear medicine, these therapies are shaping the future of prostate cancer care, offering new hope for patients with limited treatment options