Theranostics and radiopharmacy: a technical example of neuroendocrine tumour management (Gallium-68 ; Lutetium 177)

4 October 2019

F. Debordeaux, Nuclear medicine department, University Hospital Bordeaux

Theranostics and nuclear medicine are “old” partners. The theranostic approach has paved the way to personalised medicine. Isotopic molecular imaging helps to select patients who are likely to benefit from therapy. This functional imaging also determines the optimal dose of drug to be administered to the patient or ensures its therapeutic follow-up. Another objective is to be able to predict and then assess the clinical response (overall survival, progression free survival, etc.). For example, PET with 18F-FDG (fluorodesoxyglucose) is known to be a prognostic component of both conventional chemotherapy and targeted therapy. In addition, pharmacokinetic studies leads to the identification of specific populations of patients for which dosing should be adapted and may also help to provide a better understanding of treatment ineffectiveness. This is again a diagnostic and therapeutic standard in nuclear medicine, with the example of benign or malignant thyroid diseases. Iodine-123 diagnostic imaging or iodine-131 post-therapy imaging may assess therapeutic effectiveness.
Peptide receptor radionuclide therapy (PRRNT) with 177Lu-labeled somatostatin analog benefits in the same way from this theranostic approach for neuroendocrine tumour (NET) treatment. PET-CT (Positron Emission Tomography - Computed Tomography) using a gallium-68 radiolabelled somatostatin analog confirms the presence of the therapeutic target and tumour uptake.
NETs are rare and heterogeneous tumours, with different evolution profiles, but when well differentiated, overexpress somatostatin receptors. Lutatherapy associates a somatostatin receptor agonist with a therapeutic radionuclide lutetium-177. This radionuclide is characterised by a therapeutic beta - emission, but also a gamma emission that enables post-therapeutic SPECT imaging (single photon emission computed tomography).
The international multicenter study NETTER-1 led to the rise of lutatherapy in France. This open, randomised, controlled phase III study compared the anti-tumour efficiency of 177Lu-DOTA0-Tyr3-octreotate (or 177Lu-DOTATATE, Lutathera®) plus 30 mg Octreotide LAR to 60 mg Octreotide LAR in patients with inoperable, well-differentiated NET of the small bowel (midgut carcinoid tumours), grade 1 or 2, progressive, somatostatin receptor positive. Lutathera® was associated with a risk reduction of 79% of disease progression or death (median of PFS not reached but estimated at 28.4 months in the Lutathera arm whilst the median PFS was 8.4 months in the Octreotide LAR 60 mg arm). The treatment also led to a significant improvement in the quality of life described by patients.
The practical implementation of these treatments has evolved from the clinical research stage to the current marketing authorisation. This drug marketed in a single dose format may require dose adjustments. The use of an automated system reduces the exposure of agent during these highly irradiant stages of dose preparation. The procedures for administering the medicinal product have also been optimised in order to minimise the exposure of medical and paramedical workers involved.
Diagnostic PET imaging is based on the administration of 68Ga-labelled somatostatin analog. It is necessary to carry out extemporaneous preparations, because of the radionuclide fast decay. In the same way as for therapy, the evolution of the framework of clinical research towards the routine of nuclear medicine department is associated with a simplification of the labelling procedure initially in accordance with industrial good manufacturing practice. These even simplified preparations involve high-energy radionuclides, which leads to the use of the most automated techniques possible for both labelling and patient dose preparation.
Nuclear medicine therapy is experiencing a new dynamic. Lutatherapy indications are likely to expand. The identification of new molecular targets is likely to lead to the isotopic theranostic management of many other cancer pathologies.

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