Senthamizhchelvan Srinivasan, PhD, CHI Memorial Hospital, Chattanooga, TN, USA
The use of radioactive materials in medicine dates to the discovery of Radium (Ra) by Marie and Pierre Curie in 1898. In 1934, Irene and Pierre Joliot-Curie demonstrated that stable elements could be made radioactive by exposing them to highly radioactive sources that emit alpha particles or neutrons. Around the same time, Ernest O. Lawrence’s invention of the cyclotron enabled the production of radioactive isotopes by altering the nuclei of stable elements. In the 1940s, Dr. Saul Hertz at Massachusetts General Hospital, who, along with Robley Evans, demonstrated the therapeutic application of Iodine-131 (131I) and its ability to target the thyroid gland, which was a significant milestone in radiopharmaceutical therapy (RPT).
Despite its long history, RPT has only recently gained larger attention outside of nuclear medicine departments. This shift in attention is mainly driven by breakthroughs in the recent decade, including a few significant approvals by The United States Food and Drug Administration (FDA).
- Radium-223 (223Ra)-dichloride (XofigoTM): Approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with symptomatic bone metastases marked a key moment in targeted alpha therapies (TATs). Xofigo demonstrated a 30% reduction in the risk of death and significant prolongation of overall survival (OS) in the ALSYMPCA trials. It also provided symptomatic relief by reducing skeletal-related events (SREs), a routine complication in bone metastases.
- Lutetium-177 (¹⁷⁷Lu)-DOTATATE (Lutathera™): Approved based on Phase 3 NETTER-1 and NETTER-2 trials, which demonstrated substantial improvements in progression-free survival (PFS) for patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumors (NETs).
- Lutetium-177 (¹⁷⁷Lu)-PSMA-617 (Pluvicto™): Approved following the VISION trial, which showed significant gains in OS and PFS for patients with prostate-specific membrane antigen (PSMA)-expressing mCRPC.
These successes have spurred a surge of interest in developing new radiopharmaceuticals (RPs) targeting a broader range of cancer types.
Radiotheranostics:
The concept of theranostics, combining diagnostics and therapeutics, originated nearly a century ago with RPs used to image and treat cancer. Marie Curie foreshadowed this approach in 1921, believing Ra could cure deeply rooted cancer. In 1998, John Funkhouser coined the term “theranostics” to describe strategies linking diagnostics with targeted therapies. Over the past decade, radiotheranostics has revolutionized cancer treatment, particularly for prostate cancer and neuroendocrine tumors, establishing itself as the standard of care in specific cases. Radiotheranostics stands out as the only theranostic category to achieve routine clinical application. It combines radionuclide imaging (RNI) and therapy, one such example is Iodine-123 (¹²³I) for imaging and Iodine-131 (131I) for therapy.
RPs consist of distinct structural components, such as, Targeting Entities: molecules designed for specific receptor or enzyme interactions. Linkers: pharmacokinetic modifiers that optimize distribution and stability. Chelators: structures that securely bind radionuclides. Radionuclides are categorized based on their emissions, Diagnostic radionuclides: Emit gamma rays or beta particles, suitable for imaging. Therapeutic radionuclides: Emit beta-particles, alpha-particles, or Auger electrons, used in treatment. Dual-purpose radionuclides: Examples include Lutetium-177 (177Lu), Samarium-153 (153Sm) and Holmium-166 (166Ho), which primarily emit therapeutic beta-particles but also produce gamma-rays for post-therapy imaging and dosimetry. However, they are not commonly used solely for diagnostic imaging. Radiotheranostics aligns diagnostics and therapy by using nuclear imaging to confirm target affinity, ensuring patients are appropriately selected for RPTs. This integration allows for precise, personalized treatment strategies, enhancing therapeutic outcomes.
Selecting suitable radionuclides is critical for optimizing the efficacy of radiotheranostics. Radionuclides emit one or more types of particles during radioactive decay, each with distinct characteristics:
- Alpha-Particles: Composed of two protons and two neutrons, alpha-particles are relatively large, with limited penetration power (radiation range <100 micrometer). Their short range delivers highly localized, high linear energy transfer (LET) effects, ideal for targeting small clusters of cancer cells while sparing surrounding tissue.
- Beta-Particles: These high-speed electrons or positrons have slightly better penetration capabilities, with a radiation range of up to 2 mm. This allows for crossfire effects, where nearby tumor cells are affected, making them effective for larger or heterogeneous tumors.
- Auger Electrons: Emitted during inner-shell electron ionization, Auger electrons have extremely short ranges (nanometers to micrometers). Their effects are highly localized at a microscopic level, making them ideal for targeting individual cells or subcellular structures.
Understanding these emission properties is vital for predicting biological effects, optimizing therapeutic outcomes, and ensuring radiation safety. Each particle type offers unique advantages, and the choice of radionuclide must align with the clinical goal and tumor characteristics.
Emerging radionuclides for Radiopharmaceutical Therapy (RPT)
While established radionuclides like Yttrium-90 (90Y), Lutetium-177 (177Lu), and Actinium-225 (225Ac) remain central to RPTs, a new generation of radionuclides is gaining attention for its potential versatility and enhanced therapeutic outcomes. Emerging beta emitters, including Terbium-161 (161Tb), and Copper-67 (67Cu) are under clinical/pre-clinical trials, alongside targeted alpha therapies using radionuclides such as Lead-212 (212Pb), Thorium-227 (227Th), Astatine-211 (211As) and Bismuth-213 (213Bi). Terbium offers four medically relevant radioisotopes with identical chemical properties, allowing the development of radiopharmaceuticals with consistent pharmacokinetics. 161Tb, in particular, resembles 177Lu in therapeutic profile but has the added advantage of co-emitting electrons that enhance efficacy by targeting micrometastases. Early studies, such as the first-in-human use of [¹⁶¹Tb] Tb-DOTATOC, demonstrated its feasibility for imaging small metastases.
For 225Ac, effective imaging remains challenging. Lanthanum-132 (132La), a beta-emitter with similar tumor uptake and biodistribution, has been proposed as a surrogate for simulating the behavior of ²²⁵Ac-labeled agents. This surrogate approach may address limitations in tracking and dosimetry for Ac-based therapies. The expanding toolbox of radionuclides, particularly Tb isotopes, opens new possibilities in radiotheranostics by combining advanced imaging capabilities with potent therapeutic effects. These developments offer hope for more precise, effective cancer treatments while addressing current limitations in dosimetry, efficacy, and safety.
How RPTs differ from external beam radiotherapy
The administration RPT for cancer treatment differs fundamentally from conventional external beam radiation therapy (EBRT) in how radiation is delivered to tumor cells:
- Uniform vs. nonuniform dose distribution: EBRT delivers a uniform absorbed dose across the tumor site, regardless of cell density. RPT results in a nonuniform absorbed dose, with the relative dose per cell influenced by factors such as: Type of radiation emission, tumor cell density and clustering, proportion of tumor cells successfully targeted by the radiopharmaceutical and the physical and biological half-life of the radionuclide used.
- Cell-Specific targeting: While RPT may struggle to eradicate individual cancer cells completely, it excels at sparing normal tissues and is effective in targeting metastatic lesions in major organs, areas often beyond the reach of EBRT.
- Radiation dose efficiency: RPT can, in some cases, deliver a lower total radiation dose while achieving comparable clinical outcomes, further reducing the risk of damage to surrounding healthy tissues.
RPT offers unique advantages over EBRT, particularly in targeting metastases and sparing normal tissues, though its efficacy depends on optimizing radionuclide selection and delivery to maximize tumor cell absorption.
Patient specific RPT
Radiopharmaceutical therapy relies on the emission of short-range alpha-particles, beta-particles, or auger electrons to induce DNA damage within cancer cells, delivering highly localized radiation that leads to cell death. However, the current “one-size-fits-all” approach to RPT does not account for individual patient variability, which can significantly impact treatment outcomes. Each patient’s response to RPT depends on several variables, such as radiopharmaceutical biokinetics, DNA repair mechanism, tumor sensitivity, tumor volume.
Standardized treatment schedules may not maximize therapeutic potential for every patient. Personalized treatment planning, incorporating patient-specific data, could significantly enhance efficacy by tailoring dose delivery to the individual’s biological and tumor characteristics. Developing predictive mathematical models could play a critical role in personalized RPT. Such models would simulate patient-specific outcomes, optimize dosimetry which would allow for precise adjustment of administered doses to achieve optimal therapeutic outcomes. While individualized treatment planning is not yet standard practice in RPT, it could help in maximizing therapeutic efficacy while minimizing risks.
RPT toxicity profile
The targeted nature of radiopharmaceutical therapy (RPT) significantly reduces systemic side effects compared to conventional treatments like chemotherapy. However, some risks remain:
- Hematologic Toxicity: Myelosuppression is a frequent side effect, especially with therapies involving 177Lu and 223Ra.
- Organ-specific toxicity: Off-target radionuclide accumulation can lead to renal or hepatic toxicities, requiring close monitoring. There is very limited radiobiological data available for RPTs, most of dose-response data for RPTs are derived from EBRT.
- Long-Term Risks: Potential long-term effects, such as secondary malignancies, remain an area requiring further investigation.
Despite a generally favorable safety profile, meticulous patient selection and monitoring are crucial to minimizing risks, particularly for individuals with underlying comorbidities.
RPTs accessibility and cost
RPT is resource-intensive, requiring advanced infrastructure for production, handling, and administration of radioactive materials. Key challenges include:
- Radionuclide Availability: Short half-lives of therapeutic isotopes like 225Ac and Lutetium-177Lu demand efficient production and rapid distribution networks.
- Specialized facilities: Administration of RPT requires trained personnel and dedicated nuclear medicine facilities, which are not universally available.
- High costs: The complex supply chain, coupled with the novelty of RPT, makes it a costly option, potentially limiting access in low-resource settings.
Addressing these challenges is crucial for ensuring equitable access and fostering widespread adoption.
RPT has made significant progress, demonstrating its potential as a targeted and effective cancer treatment. While it has proven transformative in specific areas, broader adoption faces challenges related to logistics, cost, and regulation. Future research should prioritize developing radiopharmaceuticals for diverse disease targets. Comprehensive studies on safety, efficacy, radiobiology and long-term dose-response are crucial for RPT to become a standard treatment. Though some tracers may not reach clinical use, continued innovation in tracers will expand RPT’s clinical applications. With sustained investment, improvements in availability and affordability, RPT is poised to become standard of care for many cancer treatments. For now, its widespread adoption depends on overcoming these remaining barriers.
References
- Goldsmith SJ. Targeted Radionuclide Therapy: A Historical and Personal Review. Semin Nucl Med. 2020 Jan;50(1):87-97.
- Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.