European Nuclear Medicine Guide
Radiopharmaceutical: 177Lu-PSMA small molecule inhibitors (177Lu-PSMA-617([177Lu]Lu-PSMA-617), 177Lu-DOTAGA-(l-y)fk(Sub-KuE) aka 177Lu-PSMA I&T).
Radionuclide: Lutetium-177 is a medium-energy β-emitter with a maximum energy of 0.5 MeV, a maximal tissue penetration of 2 mm, and a half-life of 6.7 days. Lutetium-177 also emits low-energy γ-rays at 208 and 113 keV with 11% and 6.4% abundance, respectively, and this allows scintigraphy and subsequent dosimetry with the same therapeutic compound
Activity: according to guidelines the administered activity proposed per cycle is 3.7- 9.3 GBq for two-six cycles every 6-8 weeks.
Administration: intravenous (i.v.)
The EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands (177Lu-PSMA-RLT) contains recommendations for its clinical application [52].
Prostate-specific membrane antigen (PSMA) (also known as glutamate carboxypeptidase II) is a type II transmembrane glycoprotein, that is highly expressed in prostate cancer and is well correlated with tumour aggressiveness, metastatic disease, and recurrence.
Eligibility and clinical decision making should be based on multidisciplinary discussion.
Eligibility criteria include:
Commonly, treatment is preceded by a diagnostic assessment using an analogue ligand with a PET radionuclide such as [68Ga]Ga-PSMA-11.
Imaging can be performed essentially as described for [177Lu]Lu-DOTA-TATE, however, as lower amounts of radioactivity are given, there may be a need for prolonged acquisitions. Multiple SPECT/CT scanning is recommended using medium energy general purpose collimators and an energy window centred at 208 keV For performing optimal dosimetry Planar and SPECT/CT at 4, 24, 48 and 120 h is suggested [36].
In general, 177Lu-PSMA small-molecule inhibitors is administered in a fractioned approach of 2-9 GBq per cycle [204–206]. Two multicentre phase III trials are in progress, Vision ClinicalTrials.gov Identifier NCT03511664) and TheraP (ClinicalTrials.gov Identifier NCT03392428); both trials are using a fractionated approach with maximally 6 cycles of 7.4 -8.5 GBq 177Lu-PSMA-617.
One study investigated absorbed doses to metastases for177Lu]Lu-PSMA I&T and reported a range from 0.03-78 Gy/GBq with a mean value of 3.3 Gy/GBq [205].
For therapy with 177Lu-PSMA small-molecule inhibitors, dosimetry driven treatment planning could potentially ease implementation and provide large benefits for the patients. Absorbed doses to risk organs could be significant over the treatment cycles, and prospective absorbed dose measures could prove valuable in determining the acceptable number of cycles. Administrations of tracer amounts of [177Lu]Lu-PSMA-617 and pre-therapeutic dosimetry have been investigated, and the authors of this study concluded that substantial individual variance mandates patient specific dosimetry [207]. A more practical approach might be to perform treatment planning based on quantitative imaging from the previous treatment cycle or by performing pre-therapeutic diagnostic assessment using a surrogate ligand.
The dose-effect curves, with tolerance limits for normal tissue and the desirable absorbed dose to tumours, will likely need to be empirically determined. The experience from other molecular radiotherapies demonstrates that the common assumption of identical tolerance limits for MRT and EBRT can often lead to an under-dosage of radiopharmaceuticals, because the tolerance limits are actually higher. This might be explained by different dose-rates, energies, or the short range of the beta emissions which necessitate an investigation of small-scale dosimetry.
Although the survival benefits of these treatments have not yet been reported in randomized clinical trials, efficacy can be evaluated by biochemical response defined by decline in prostate-specific antigen (PSA), response assessed by PET/CT imaging, radiologic response, pain relief, or quality of life. In a German multicentre study, 45 % of the patients had a 50% decline in PSA after 1-4 therapy cycles of [177Lu]Lu-PSMA-617 [208]. Several other trials have also demonstrated high efficacy for small-molecule inhibitors in patients with metastatic castration-resistant prostate cancer [205,209,210].
No study has yet reported comparisons of absorbed doses to response or toxicity of treatment with[177Lu]Lu-PSMA small molecule inhibitors. Doses absorbed by normal tissue were shown not to differ significantly between therapy cycles, but it still remains to be investigated whether Gy/GBq values from the first cycle can be used directly for treatment planning of subsequent cycles [211]. Prospective imaging with positron-emitting surrogate markers could deviate from the actual biodistribution.
Further possibilities for development include combination treatments.
Investigations of Iodine-131 and Yttrium-90 based ligands have also been performed, but the current focus is on Lutetium-177 radiolabelled ligands and especially small-molecule inhibitors. Since the radiotherapeutics are still in clinical trials, no standard treatment regimens have been developed.
In studies of SPECT/CT based dosimetry for [177Lu]Lu-PSMA-617, the salivary/parotid glands (1.2-1.4 Gy/GBq) and kidneys (0.6-1.0 Gy/GBq) were the organs which received the highest mean absorbed doses [207,210,211]. Mean absorbed doses to red marrow were reported between 12 and 48 mGy/GBq. The lacrimal glands might also represent a dose-limiting organ [212]. For [177Lu]Lu-PSMA I&T, similar absorbed doses are observed: 1.3 Gy/GBq for parotid glands, 0.8 Gy/GBq for kidneys, and 14 mGy/GBq for red marrow [205].
All the ligands targeting PSMA and labelled with Lutetium-177 are still in an investigational phase in most countries ([177Lu]Lu-PSMA-617 has been approved for clinical use in Switzerland in 2018 and is currently performed outside any clinical trial).