Radiotheranostics - Precision Medicine in Nuclear Medicine and Molecular Imaging

Abstract

'See what you treat and treat what you see, at a molecular level', could be the motto of theranostics. The concept implies diagnosis (imaging) and treatment of cells (usually cancer) using the same molecule, thus guaranteeing a targeted cytotoxic approach of the imaged tumor cells while sparing healthy tissues. As the brilliant late Sam Gambhir would say, the imaging agent acts like a 'molecular spy' and reveals where the tumoral cells are located and the extent of disease burden (diagnosis). For treatment, the same 'molecular spy' docks to the same tumor cells, this time delivering cytotoxic doses of radiation (treatment). This duality represents the concept of a 'theranostic pair', which follows the scope and fundamental principles of targeted precision and personalized medicine. Although the term theranostic was noted in medical literature in the early 2000s, the principle is not at all new to nuclear medicine. The first example of theranostic dates back to 1941 when Dr. Saul Hertz first applied radioiodine for radionuclide treatment of thyroid cells in patients with hyperthyroidism. Ever since, theranostics has been an integral element of nuclear medicine and molecular imaging. The more we understand tumor biology and molecular pathology of carcinogenesis, including specific mutations and receptor expression profiles, the more specific these 'molecular spies' can be developed for diagnostic molecular imaging and subsequent radionuclide targeted therapy (radiotheranostics). The appropriate selection of the diagnostic and therapeutic radionuclide for the 'theranostic pair' is critical and takes into account not only the type of cytotoxic radiation emission, but also the linear energy transfer (LET), and the physical half-lives. Advances in radiochemistry and radiopharmacy with new radiolabeling techniques and chelators are revolutionizing the field. The landscape of cytotoxic systemic radionuclide treatments has dramatically expanded through the past decades thanks to all these advancements. This article discusses present and promising future theranostic applications for various types of diseases such as thyroid disorders, neuroendocrine tumors (NET), pediatric malignancies, and prostate cancer (PC), and provides an outlook for future perspectives.

Figure 1

55-year-old man with pancreatic NET, first diagnosed in September 2017 without hormone hypersecretory syndrome. Initial staging was pT3 N1 M1 to the liver with a ki-67 of 18.4%, grade 2. The patient underwent distal pancreatectomy, splenectomy and right hepatic lobectomy, and subsequent chemotherapy with everolimus. Restaging showed progression of liver metastases and chemotherapy with temozolomide and capecitabine was initiated. However, the liver metastases were unresponsive to chemotherapy. The patient was evaluated for PRRT and showed SSR expression. Subsequent treatment with four cycles of ¹⁷⁷Lu-DOTATATE. Pretreatment ⁶⁸Ga-DOTATATE PET showed liver-only disease: A) axial and B) maximum intensity projection (MIP) ⁶⁸Ga-DOTATATE PET. Post ¹⁷⁷Lu-DOTATATE treatment SPECT confirmed treatment targets: C) planar anterior and D) posterior view of ¹⁷⁷Lu-DOTATATE SPECT. Post-therapeutic whole-body SPECT/CT was obtained for treatment evaluation and dosimetric purposes. Interval ⁶⁸Ga-DOTATATE PET after two treatment cycles showed decreased size of liver metastases with central necrosis: E) axial and F) MIP ⁶⁸Ga-DOTATATE PET.

Figure 2

32-year-old woman with progressive metastatic osteosarcoma to the pleura, first diagnosed in February 2019. She underwent resection of the primary tumor in the right knee and multiple lines of chemotherapy. As her disease burden markedly increased with extensive right pleural metastases, few left pleural metastases, and right internal mammary, mediastinal, and hilar nodal metastases, she was referred for ²²³Ra treatment under compassionate care. Pretreatment Na-¹⁸F PET/CT showed uptake in the pleura: A) Axial Na-¹⁸F PET, B) axial fused Na-¹⁸F PET/CT, C) MIP Na-¹⁸F PET. Post ²²³Ra therapy SPECT/CT evidenced uptake of ²²³Ra in the calcified osteosarcoma lesions in the pleura: D) axial ²²³Ra-SPECT, E) axial fused ²²³Ra-SPECT/CT, F) MIP ²²³Ra-SPECT/CT. The recent Na-¹⁸F PET/CT after three cycles of ²²³Ra showed stable disease: G) axial Na-¹⁸F PET, H) axial fused Na-¹⁸F PET/CT, I) MIP Na-¹⁸F PET.

Figure 3

Post-therapeutic ¹³¹I-mIBG SPECT/CT of an 8-year-old boy with progressive refractory metastatic stage IV ganglioneuroblastoma. After initial ¹³¹I-mIBG SPECT/CT showed ¹³¹I-mIBG uptake in the sites of progressive disease in the hemimandible, femur, proximal tibia, and 7^th rib, all right sighted, and mastoid left, the patient received ¹³¹I-mIBG therapy. A) Axial ¹³¹I-mIBG SPECT, B) axial fused ¹³¹I-mIBG SPECT/CT, C) MIP ¹³¹I-mIBG SPECT. The post-therapeutic scan served as treatment verification and was used for dosimetry. ¹³¹I-mIBG SPECT/CT showed uptake of ¹³¹I-mIBG in the aforementioned sites of disease.