Radiotheranostics: a roadmap for future development

Abstract

Radiotheranostics, injectable radiopharmaceuticals with antitumour effects, have seen rapid development over the past decade. Although some formulations are already approved for human use, more radiopharmaceuticals will enter clinical practice in the next 5 years, potentially introducing new therapeutic choices for patients. Despite these advances, several challenges remain, including logistics, supply chain, regulatory issues, and education and training. By highlighting active developments in the field, this Review aims to alert practitioners to the value of radiotheranostics and to outline a roadmap for future development. Multidisciplinary approaches in clinical trial design and therapeutic administration will become essential to the continued progress of this evolving therapeutic approach.

Figure 1:. Revenue growth of the radiotheranostics field

Adapted with permission from Paul-Emmanuel Goethals and Richard Zimmermann (Nuclear Medicine MEDraysintell Report & Directory, July 2019). New radiotheranostics that are not yet approved, but whose approval is expected in the future are indicated after 2020. PSMA=prostate-specific membrane antigen.

Figure 2:. Overview of different radiotheranostic constructs

Theranostic radiopharmaceuticals are commonly designed to carry α or β emitters to cancers, which is achieved by attaching targeting ligands (small molecules, peptides, or antibodies) to chelators that complex radioisotopes for systemic delivery. Alternatively, radioiodine is attached directly to targeting ligands. Another application is to deliver micron-sized embolic particles containing ⁹⁰Y to cancers using catheter based intra-arterial delivery.

Figure 3:. Examples of patients with well-differentiated neuroendocrine tumours undergoing ¹⁷⁷Lu-dotatate treatment

After four cycles of ¹⁷⁷Lu-dotatate therapy a corresponding ⁶⁸Ga-dotatate PET/CT scan reveals remission in a responder and progression in a non-responder (10 months between images). Responder: patient with a pancreatic neuroendocrine tumour (Ki67 of20%) showing disease progression. Non-responder: patient with a well differentiated ileal neuroendocrine tumour (Ki67 of 1%) presenting with liver metastases and peritoneal carcinomatosis. Progressive disease is still seen after four cycles of ¹⁷⁷Lu-dotatate.

Figure 4:. CXCR-4-directed radiotheranostics in a patient with intramedullary and extramedullary multiple myeloma

(A) Maximum-intensity projections of ⁶⁸Ga-pentixafor and ¹⁸F-labeled fluoro-2-deoxyglucose (¹⁸F-FDG) PET/CT indicate multiple extramedullary and intramedullary ¹⁸F-FDG-avid myeloma lesions with high CXCR-4 expression. Corresponding ¹⁸F-FDGPET/CT image 14 days after ⁹⁰Y-pentixather treatment shows complete metabolic response compared with images before therapy. (B) Scintigraphic images of a patient with multiple myeloma at 24 h and 14 days after 15.2 GBq of ¹⁷⁷Lu-pentixather. This figure shows how ligand binding to CXCR-4 is retained for 14 days after injection. The imaging does not provide any information on the success or failure of treatment. Visual differences in tumour-to-background ratios at both time points are because of reduced background uptake at the later time point and longer emission times to account for lower particle counts. Adapted and reprinted with permission from Hermann et al (2016).