European Nuclear Medicine Guide
Radiopharmaceutical: [225Ac]Ac-PSMA-617
Radionuclide: Actinium-225 has a half-life of 9.9 days. Its predominant decay path results in four alpha particles with energies ranging from 5.8 to 8.4 MeV. The tissue penetration ranges between 47 and 85 µm. Moreover, the decay cascade contains two beta disintegrations of 1.8 and 0.6 MeV maximum energy. In addition, gamma co-emissions for possible in vivo imaging are generated from the disintegration of Francium-221 (218 keV, 11.6% emission probability) and Bismuth-213 (440 keV, 26.1% emission probability) [213].
Activity: 100 kBq per kg /body weight per cycle
Administration: intravenous (i.v.)
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 [214].
Adapted from EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands ([177Lu]Lu-PSMA-ligands [52].
Eligibility and clinical decision making should be based on multidisciplinary discussion (i.e. multidisciplinary tumour board involving uro-/oncology, nuclear medicine and radiation oncology). Eligibility criteria include:
An evidence based prospective comparison of [177Lu]Lu-PSMA-ligands vs. [225Ac]Ac-PSMA-617 is not yet available, however it is suggested that patients with disseminated bone marrow involvement might benefit more from the alpha-emitter based therapy. Also casuistic suggests a possible positive effect of [225Ac]Ac-PSMA-617 in patients not responding well to [177Lu]Lu-PSMA-617 [215].
Commonly, treatment is preceded by a diagnostic assessment with radioligand-PSMA PET/CT or SPECT/CT.
Commonly, treatment is preceded by a diagnostic assessment using an analogue ligand with a PET radionuclide such as [68Ga]Ga-PSMA-11.
Posttherapy 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. [225Ac]Ac-PSMA-617 scans can be acquired using g-coemission of Bismuth-213, Francium-221 (12%), and the bremsstrahlung of Lead-209 [215].
Multiple SPECT/CT windows scanning is recommended using high energy or ultra-high energy collimators.
The recommended way to deliver [225Ac]Ac-PSMA-617 is in a fractioned approach of 100 kBq/kg/body weight per cycle repeated every 8 weeks. In one study, preliminary dosimetry estimations were calculated by extrapolating data obtained with 177Lu-PSMA-617 imaging and assuming no translocation of daughter radionuclides in the decay chain of actinium-225. Authors reported that salivary glands (2.3 Gy/MBq considering a RBE of 5), kidneys (0.7 Gy/MBq considering a RBE of 5), and red marrow (0.05 Gy/MBq considering a RBE of 5) are potentially dose-limiting organs [216]. (RBE = Radiobiological Effectiveness). These dosimetry estimates should be considered cautiously and confirmation by other studies are needed.
In contrast, in a group of chemotherapy-naïve patients an escalating/deescalating dose approach was applied. Starting with primary activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq or 4 MBq in cases of good response. In case of non-responding patients, activity was escalated up to 13 MBq [217].
Similar to treatment with [177Lu]Lu-PSMA-ligands, dosimetry driven treatment planning for [225Ac]Ac-PSMA-617 could potentially ease implementation and provide 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. A 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.
So far, there is only very limited data on the effectiveness of treatment with [225Ac]Ac-PSMA-617 [214].
Kratochwil et al. enrolled 40 patients with mCRPC for treatment with three 100 kBq/kg cycles of [225Ac]Ac-PSMA-617 at 2-months intervals [218]. Clinical follow-up was performed in 38 patients at least 8 weeks after completion of the therapy. Among them 24 (63%) had a PSA decline of more than 50%, and 33 (87%) had a PSA response of any degree. The median duration of tumour control under [225Ac]Ac-PSMA-617 therapy was 9 months. Swimmer-plot analysis indicated a promising duration of tumour control, especially considering the unfavourable prognostic profile of the selected advanced-stage patients.
Sathekge at al. applied [225Ac]Ac-PSMA-617 therapy in 17 patients with chemotherapy-naïve mCRCP [217]. They performed a deescalating dose approach as described above. The treatment resulted in a ≥ 90% decline in serum PSA in 82% of patients including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy. The remarkable therapeutic efficacy in patients who have declined chemotherapy necessitates further exploration in larger clinical trials.
Due to the limited number of treated patients there is also limited data on related side effects. Thus, in addition to the below mentioned side effects, further long-term adverse reactions may occur, which are still unknown due to insufficient follow-up data. Based on the tracer characteristics and dosimetry findings, xerostomia, bone marrow suppression, and renal impairments are the most relevant complications that may be appeared after [225Ac]Ac-PSMA-617 therapy.
Kratochwil et al. reported xerostomia after treatment with an activity of 100 kBq/kg [225Ac]Ac-PSMA-617 or more per cycle [216]. It was considered intolerable with activities greater than 150 kBq/kg [225Ac]Ac-PSMA-617. Application of lower activities such as 50 kBq/kg [225Ac]Ac-PSMA-617 were nontoxic, but provided insufficient anti-cancerous effects.
Sathekge et al. reported that the treatments were well tolerated by all patients without any acute toxicity [217]. No patients discontinued treatment due to side effects. In addition, they did not find statistically significant differences between the pre-treatment and follow-up values of leucocyte count, haemoglobin level, platelet count, serum creatinine level, or serum albumin level. However, all patients experienced grade 1-2 xerostomia.
All the ligands targeting PSMA and labelled with 225Ac are still in an early investigational phase. [218]