Radiotheranostics in oncology: current challenges and emerging opportunities

Abstract

Structural imaging remains an essential component of diagnosis, staging and response assessment in patients with cancer; however, as clinicians increasingly seek to noninvasively investigate tumour phenotypes and evaluate functional and molecular responses to therapy, theranostics - the combination of diagnostic imaging with targeted therapy - is becoming more widely implemented. The field of radiotheranostics, which is the focus of this Review, combines molecular imaging (primarily PET and SPECT) with targeted radionuclide therapy, which involves the use of small molecules, peptides and/or antibodies as carriers for therapeutic radionuclides, typically those emitting α-, β- or auger-radiation. The exponential, global expansion of radiotheranostics in oncology stems from its potential to target and eliminate tumour cells with minimal adverse effects, owing to a mechanism of action that differs distinctly from that of most other systemic therapies. Currently, an enormous opportunity exists to expand the number of patients who can benefit from this technology, to address the urgent needs of many thousands of patients across the world. In this Review, we describe the clinical experience with established radiotheranostics as well as novel areas of research and various barriers to progress.

Fig. 1 |. Overview of the concept of radiotheranostics.

Radiopharmaceuticals are paired with targeted ligands to ‘see with precision’ and then ‘treat with targeting’.

Fig. 2 |. Responses to approved theranostics, as demonstrated using their imaging counterpart.

a | Coronal PET ⁶⁸Ga-DOTATATE maximum-intensity projection (MIP) depicting a patient with an atypical bronchial carcinoma, with disease progression on everolimus with extensive osseous (blue solid arrows) and hepatic (dashed arrows) metastases. b | After four cycles of ¹⁷⁷Lu-DOTATATE, a marked reduction in both the number and extent of bone and liver lesions can be observed. c,d | Coronal PET ⁶⁸Ga-PSMA-11 MIP (panel c) and fused axial PET–CT images (panel d) depicting a patient with Gleason grade 9 prostate cancer with extensive retroperitoneal and pelvic nodal metastases following radical prostatectomy, androgen-deprivation therapy and abiraterone. e | After five cycles of ¹⁷⁷Lu-PSMA-617, the adenopathy is markedly decreased in size. f | Fused axial PET–CT images provide a more detailed view of the pelvic nodal metastases after ¹⁷⁷Lu-PSMA, with several nodes that are visible in panel d no longer present in panel f. g,h | Anterior (panel g) and posterior (panel h) coronal PET ^99mTc-MDP MIPs depicting a patient with de novo metastatic Gleason grade 9 prostate cancer with metastatic lesions located in the spine, ribs, pelvis and femur. i,j | After six cycles of ²²³Ra-dichloride, a decreased intensity of uptake can be observed at all metastatic sites.

Fig. 3 |. The predicted global nuclear medicine market 2013–2026.

This projected market growth likely reflects the availability of a greater number of agents, implementation at an increasing number of centres and projected increases in the numbers of patients with cancer globally. ©MEDraysintell Nuclear Medicine Report C Directory, Edition 2021. CRPC, castration-resistant prostate cancer; mCRPC, metastatic CRPC; NET, neuroendocrine tumour; PSMA, prostate-specific membrane antigen.

Fig. 4 |. Therapeutic approaches involving radiotheranostics.

Therapeutic effects on cancer cells caused by DNA damage induced by either α-, β- or auger-emitting radionuclides can be enhanced via combination with drugs that either cause direct damage to DNA (such as chemotherapies) or inhibit DNA damage repair directly (such as PARP inhibitors) or through modulation of the associated signalling pathways (such as novel androgen-deprivation therapies). Radiotheranostics can also target the tumour microenvironment (such as cancer-associated fibroblasts (CAFs)) and kill stromal cells, which can indirectly lead to tumour regression. Bystander effects, owing to use of β-emitters, on the DNA of cancer cells that do not express radiotheranostic target proteins can nonetheless lead to tumour cell death. Targeted radionuclide therapies might also induce antigen presentation following cancer cell death and, when combined with immune-checkpoint inhibitors, lead to enhanced antitumour activity. DDR, DNA damage response.