A Review of Theranostics: Perspectives on Emerging Approaches and Clinical Advancements

Abstract

Theranostics is the combination of two approaches-diagnostics and therapeutics-applied for decades in cancer imaging using radiopharmaceuticals or paired radiopharmaceuticals to image and selectively treat various cancers. The clinical use of theranostics has increased in recent years, with U.S. Food and Drug Administration (FDA) approval of lutetium 177 (¹⁷⁷Lu) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE) and ¹⁷⁷Lu-prostate-specific membrane antigen vector-based radionuclide therapies. The field of theranostics has imminent potential for emerging clinical applications. This article reviews critical areas of active clinical advancement in theranostics, including forthcoming clinical trials advancing FDA-approved and emerging radiopharmaceuticals, approaches to dosimetry calculations, imaging of different radionuclide therapies, expanded indications for currently used theranostic agents to treat a broader array of cancers, and emerging ideas in the field. Keywords: Molecular Imaging, Molecular Imaging-Cancer, Molecular Imaging-Clinical Translation, Molecular Imaging-Target Development, PET/CT, SPECT/CT, Radionuclide Therapy, Dosimetry, Oncology, Radiobiology © RSNA, 2023.

Keywords: Dosimetry; Molecular Imaging; Molecular Imaging–Cancer; Molecular Imaging–Clinical Translation; Molecular Imaging–Target Development; Oncology; PET/CT; Radiobiology; Radionuclide Therapy; SPECT/CT.

Figure 1:

Radionuclide therapy schematic. A radionuclide held in a chelator or cage or bound covalently is attached to a vector by a linker molecule. The vector binds to a molecular target to enable visualization of the target for diagnostic or treatment purposes and selective delivery of radiation therapy to the target. Alternatively, a free radionuclide ion can, in some circumstances, be used to target tumors or cancer cells, as with iodine 131, alastine 211, and radium 223. Created with BioRender.com.

Figure 2:

Targeted α-particle therapy schematic. The radionuclide therapy is intravenously infused and binds to the tumor through a vector linked to the radionuclide. While bound to the tumor, α-particle emission occurs, selectively delivering radiation to the tumor. α Particles are more cytotoxic than β particles because they cause irreparable double-strand DNA breaks, resulting in cell death. Created with BioRender.com.

Figure 3:

Targeted β-particle therapy schematic. While bound to the tumor, β-particle emission occurs, selectively delivering radiation to the tumor. β Particles exert therapeutic effects through reactive oxygen species, causing DNA damage via single-strand DNA breaks that may result in cell death if not repaired via DNA repair mechanisms. Created with BioRender.com.

Figure 4:

Targeted α-particle and β-particle therapy comparison. Illustration shows the characteristic features of α and β particles. α Particles are positively charged particles composed of two protons and two neutrons, essentially the nucleus of a helium atom, and β particles are negatively charged particles, essentially electrons. α Particles have much greater mass, higher linear energy transfer (LET), travel a much shorter distance in tissue, and are more cytotoxic than β particles. The illustration includes specific values of these characteristics for reference but is not to scale. Created with BioRender.com.

Figure 5:

Targeted α-particle therapy: radium 223 dichloride (²²³RaCl₂) followed by actinium 225 (²²⁵Ac) prostate-specific membrane antigent (PSMA)–617. Images in a 66-year-old man with widely metastatic prostate cancer, with a Gleason score of 8 (4 + 4), that progressed following androgen deprivation, chemotherapy, and pelvic radiation. (A) Baseline gallium 68 (⁶⁸Ga) PSMA-11 PET/CT image demonstrates intense PSMA uptake in numerous metastatic lesions (blue arrows indicate examples in the right scapula and both femurs). (B) ⁶⁸Ga-PSMA-11 PET/CT image following three cycles of ²²³RaCl₂ (a targeted α-particle therapy that incorporates within osteoblastic lesions but does not directly bind to cancer cells) shows progression of many osseous metastases (blue arrows), and the prostate-specific antigen (PSA) value increased. (C) Lutetium 177 (¹⁷⁷Lu) PSMA-617 and ²²⁵Ac-PSMA-617 were both considered as treatment options. Following multidisciplinary discussion and shared decision-making with the patient, four cycles of ²²⁵Ac-PSMA-617 (a targeted α-particle therapy with affinity for PSMA) were administered 6 weeks apart, demonstrating dramatic response in the metastatic lesions, with near resolution of PSMA uptake at ⁶⁸Ga-PSMA-11 PET/CT (blue arrows in the location of previous lesions) and a corresponding dramatic reduction in PSA.

Figure 6:

Posttherapy monitoring of index lesions with SPECT/CT imaging. Fused SPECT/CT sagittal images in a 56-year-old man with prostate-specific membrane antigen (PSMA)–avid metastatic prostate cancer undergoing lutetium 177 (¹⁷⁷Lu) PSMA-617 therapy. (A) Baseline fluorine 18 (¹⁸F) carboxy-fluoro-pyridine-carbonyl-amino-pentyl-ureido-pentanedioic acid (DCFPyL) PET/CT image demonstrates intense PSMA uptake in nodal, osseous, and hepatic metastases (arrows). (B–E) Posttherapy SPECT/CT image with ¹⁷⁷Lu-PSMA-617 was performed approximately 24 hours after infusion of the therapeutic radiotracer after each of four cycles administered 6 weeks apart, demonstrating localization of the therapeutic radiopharmaceutical to the metastases. Index lesions in lymph node, bone, and liver (arrows) demonstrate decreased intensity of uptake with each cycle of therapy. (C) After cycle 2, the hepatic and nodal metastases were no longer conspicuous, and (E) after cycle 4, the spine metastasis was no longer conspicuous. Imaging the therapeutic radionuclide enables confirmation of effective delivery to the sites of cancer and detection of treatment response over the course of therapy, demonstrated by the changes in the imaged index lesions over time.

Figure 7:

Complete treatment response after two cycles of lutetium 177 (¹⁷⁷Lu) prostate-specific membrane antigen (PSMA)–617 therapy. Images in a 63-year-old man with widely metastatic prostate cancer, with a Gleason score of 9 (4 + 5). (A) Gallium 68 (⁶⁸Ga) PSMA-617 PET/CT maximum intensity projection image demonstrates widespread metastatic disease, such as numerous bone lesions (blue arrows indicate select examples). (B) Following chemotherapy and hormonal therapy, persistent PSMA-avid metastatic lesions are observed on ⁶⁸Ga-PSMA-11 PET/CT image, with slight reduction in prostate-specific antigen level. (C) Following two cycles of ¹⁷⁷Lu-PSMA-617, there is complete resolution of metastatic PSMA uptake, with undetectable PSA. Blue arrows in the expected location of previous nodal uptake show the resolved lesions on ⁶⁸Ga-PSMA-11 PET/CT image.

Figure 8:

Images in a 68-year-old man with metastatic pheochromocytoma treated with four cycles of lutetium 177 (¹⁷⁷Lu) tetraazacyclododecane tetraacetic acid octreotate (DOTATATE). A right adrenal pheochromocytoma was resected 2 years previously, with subsequent development of hepatic, osseous, and pulmonary metastasis and inferior vena cava (IVC) tumor thrombus. Selected gallium 68 (⁶⁸Ga) DOTATATE PET/CT fusion images show a DOTATATE-avid (A) pulmonary metastasis (arrow), (B) IVC tumor thrombus (arrow), and (C) hepatic metastasis (arrow). Following completion of off-label ¹⁷⁷Lu-DOTATATE therapy, (D) the pulmonary metastases (arrow), (E) IVC tumor thrombus, and (F) hepatic metastasis decreased in radiotracer uptake level. Central photopenia indicating tumor necrosis increased with the treated hepatic metastasis (E, arrow). SUV_max = maximum standardized uptake volume.

Figure 9:

Actinium 225 (²²⁵Ac) prostate-specific membrane antigen (PSMA) α-particle therapy following lutetium 177 (¹⁷⁷Lu) PSMA-617 β-particle therapy. Images in a 71-year-old man with widely metastatic prostate cancer, with a Gleason score of 7 (3 + 4), that progressed despite androgen deprivation therapy, taxane-based chemotherapy, and thoracic spine stereotactic radiation. (A) Baseline gallium 68 (⁶⁸Ga) PSMA-11 PET/CT image demonstrates intense PSMA uptake in many nodal metastases (blue arrows). (B) Following three cycles of the targeted β-particle therapy with ¹⁷⁷Lu-PSMA-617, the ⁶⁸Ga-PSMA-11 PET/CT image demonstrates persistent PSMA-avid disease (blue arrows), with a mild reduction in prostate-specific antigen (PSA). (C) Following three cycles of the targeted α-particle therapy with ²²⁵Ac-PSMA-617, nearly complete resolution of uptake in the nodal metastases is observed (blue arrows in the location of previous nodal uptake), with a substantial reduction in PSA level.