Theranostics integrates diagnostic and therapeutic radiopharmaceuticals targeting the same molecular structures – delivering a ‘one-two punch’ for personalised cancer care. In his latest commentary, Professor Alain Astier discusses how the radionuclide 177Lu and 177Lu-based radioligands have gained traction in treating various conditions, including neuroendocrine tumours and metastatic prostate cancer.
Theranostics – the integration of diagnosis and therapy – has redefined personalised medicine by enabling the simultaneous detection and treatment of malignancies. Historically, the development of theranostic agents has paralleled advances in radiochemistry and imaging technologies.
Although theranostics has been recognised in nuclear medicine for many years because of the use of radioiodine in differentiated thyroid cancer, it is only in recent years that the term has gained more widespread usage.
Lutetium: a key radionuclide with therapeutic and diagnostic utility
Lutetium (Lu; atomic number 71) is classified as a rare earth metal of the lanthanide series.
The radionuclide Lutetium-177 (177Lu) is produced predominantly by the high-flux neutron activation of 176Lu in a nuclear reactor.1 Its half-life is 6.647 days.
This radionuclide is a medium-energy beta emitter with a maximum energy of 0.497 MeV and a low-energy gamma emitter, primarily at 208 keV and 113 keV.
The initial paper outlining 177Lu as a potential diagnostic agent was published in 1968.2 The potential therapeutic properties of 177Lu are rooted in its ability to deliver localised cytotoxic radiation in relatively small tumours and metastatic lesions. Its scintigraphic imaging ability, enabled by low-energy gamma-rays, allows for subsequent dosimetry with the same therapeutic compound.3
The unique characteristics of 177Lu have enabled it to surmount many limitations of earlier radionuclides, and advancements in chelation techniques have further improved its stability and binding efficiency to various targeting ligands, optimising its therapeutic index.4
When conjugated to peptides or small molecules that specifically bind to receptors on tumour cells, such as somatostatin receptors or prostate-specific membrane antigens, beta radiation promotes the apoptosis of tumour cells, leading to the release of tumour antigens and the induction of a tumour-specific systemic immune response.5 Emerging evidence suggests that this provides a rationale for combining radioligand therapy with immunotherapeutic agents.5
Application in neuroendocrine tumours and prostate cancer
177Lu was initially introduced for the treatment of neuroendocrine tumours through peptide receptor radionuclide therapy; however, its role has broadened to encompass applications in prostate cancer and other malignancies.6,7
It is increasingly used in specific internal radiotherapy – an innovative, minimally invasive procedure designed to deliver high doses of localised radiation directly to tumours.8
The combination of 177Lu with the somatostatin analogue dotatate (177Lu-Dotatate) delivers ionising radiation that specifically targets tumour cells expressing somatostatin receptors. This causes radiation-induced single- and double-stranded DNA breaks, leading to apoptosis. Consequently, it has become a standard treatment for patients with gastro-entero-pancreatic neuroendocrine tumours, with clinical trials demonstrating significant improvements in progression-free survival and quality of life.9
In prostate cancer, 177Lu coupled with prostate-specific membrane antigen (177Lu-PSMA-617) has emerged as a promising therapy for metastatic castration-resistant disease, where recent studies report substantial reductions in prostate-specific antigen levels and manageable toxicity profiles.10
Early-phase trials are additionally investigating the synergistic effects of combining 177Lu-PSMA with external beam radiotherapy and immunotherapy, indicating a new era of combination treatments for advanced cancers.11
Limitations of 177Lu
Nonetheless, challenges persist. Producing high-specific-activity 177Lu requires advanced nuclear reactor facilities, and supply chain constraints may limit its availability.
As with most innovative cancer treatments, cost continues to be a concern, although an economic analysis of 177Lu-PSMA-617 demonstrated significant advantages in terms of quality-adjusted life years when compared with standard care in the VISION trial for metastatic prostate cancer.12
Ongoing research seeks to tackle these challenges by developing improved radiochemistry methods, novel targeting molecules with higher receptor affinity, and advanced dosimetry protocols – often incorporating artificial intelligence – to optimise personalised treatment planning.
Collaborative efforts between regulatory agencies and industry stakeholders are also underway to streamline production and distribution, which could further broaden clinical access to 177Lu-based therapies. Recent studies indicate that combining 177Lu with immunotherapy or other treatment modalities may further enhance clinical outcomes.13
Conclusions
As research continues to fuel innovation, 177Lu-based theranostics are expected to expand their applications, offering increasingly effective and personalised treatment options for cancer patients worldwide.
Regardless, 177Lu exemplifies how a single radionuclide can bridge diagnostic imaging and targeted therapy. Its favourable physical properties and robust clinical data from longstanding studies and recent trials underscore its pivotal role in modern oncology. Although production and dosimetric challenges persist, ongoing advances in radiochemistry, imaging and personalised treatment planning are set to enhance its clinical impact further.
Thus, radiopharmacy and radiopharmacists are essential in the field of theranostics for the on-demand preparation and quality assurance of medications that combine short-half-life radionuclides with targeting molecules.
Author
Alain Astier PharmD PhD
Honorary head of the Department of Pharmacy, Henri Mondor University Hospital, and French Academy of Pharmacy, Paris, France
References
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