European Nuclear Medicine Guide
Radiopharmaceutical: [225Ac]Ac-PSMA-617
Radionuclide: Actinium-225 has a physical 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) [12].
Activity: 100 kBq/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 [13]. PSMA-617 is a ligand of PSMA with high affinity. Actinium-225, usually chelated with DOTA, is responsible for the radiobiological effect of the drug, causing DNA damage to tumour cells. High energy released by the alpha particles present with a short path length and high linear energy transfer causes double-strand DNA breaks leading to tumour cells while sparing normal tissue.
Adapted from EANM procedure guidelines for radionuclide therapy with 177Lu-labelled PSMA-ligands ([177Lu]Lu-PSMA-ligands [1].
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:
Patients with metastatic, castration-resistant prostate cancers (mCRPC) who have exhausted or are ineligible for approved alternative options.
Medical history report from the (referring) physician containing a summary of all previous treatments.
Adequate anatomical imaging (e.g. computed tomography (CT) and/or magnetic resonance imaging (MRI)), not older than 3 months, preferably less than 2 months.
Baseline PSMA-ligand PET/CT (68Ga-PSMA or 18F-PSMA PET/CT) confirming high PSMA expression (uptake in metastatic lesions higher than that of normal liver uptake).
Life expectancy > 6 months
ECOG performance status ≤2
Unmanageable urinary tract obstruction or hydronephrosis; in patients with diagnosed or who are at high risk of urinary retention, [99mTc]Tc-MAG3 or [99mTc]Tc-DTPA renal scintigraphy should be considered as a baseline exam.
Progressive deterioration of organ function (GFR < 30 mL/min or creatinine > 2-fold upper limit of normal (ULN); liver enzymes > 5-fold ULN).
Myelosuppression:
Total white cell count <2.5 × 109/L
Platelet count <75 × 109/L
In serious conditions which require timely interventions (radiation therapy, surgery), e.g. spinal cord compression and unstable fractures, PSMA-directed radioligand therapy might be performed afterwards. Borderline cases should be evaluated within the multidisciplinary tumour board for the individual benefit-to-risk ratio.
Commonly, treatment is preceded by a diagnostic assessment using an analogue ue ligand with a PET radionuclide such as [68Ga]Ga-PSMA-11.
Posttherapy imaging can be performed however, as lower amounts of radioactivity are given, it is quite challenging and needs prolonged acquisitions. [225Ac]Ac-PSMA-617 scans can be acquired using gamma emission of Bismuth-213, Francium-221 (12%), and the bremsstrahlung of Lead-209 [14].
Multiple SPECT/CT windows scanning is recommended using high energy or ultra-high energy collimators.
However, clinical added value of these post-therapeutic images, out of clinical trials, remains uncertain.
The recommended activity is intra-venous injection of 100 kBq/kg body weight every 6 to 8 weeks up to remission, disease progression or unmanageable toxicity.
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 [15]. (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 [16].
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. Nevertheless, the challenges of performing dosimetry in alpha emitters limit its use in clinical practice.
So far, around 1000 patients treated with [225Ac]Ac-PSMA-617 have been reported in the literature.
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 [17]. 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 et al. applied [225Ac]Ac-PSMA-617 therapy in 17 patients with chemotherapy-naïve mCRCP [16]. 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.
Sathekge et al. enrolled 488 patients in an international multicentric retrospective study with mCRPC treated with one or more cycles of 8 MBq of [225Ac]Ac-PSMA-617 every eight weeks [38]. Patients received previous lines of treatment with chemotherapy (docetaxel for 66% of the patients, cabazitaxel 21%), new hormone therapy (abiraterone 39%, enzalutamide 39%) and radionuclide therapy (177Lu-PSMA 32%, 223RaCl2 4%) [18]. 89% of the treated population presented with bone metastases. Treatment with [225Ac]Ac-PSMA-617 was stopped due to remission, disease progression, death or patients withdrawal. Patients received a median of 2 cycles (IQR 2-4). With a median follow-up of 9 months (IQR 5·0–17·5), median overall survival was 15.5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). 278 patients (57%) had a ≥50% PSA decline. The following factors were significantly associated with overall survival : PSA response, metastatic pattern of the disease, previous lines of treatment, anaemia at baseline.
A recent meta-analysis of Dai et al (1) (meta-analysis of 13 studies, 885 patients) treated with [225Ac]Ac-PSMA showed a 50% PSA decline across all cycles for 60% of patients. Patients treated with [225Ac]Ac-PSMA were followed for a median period ranging from 5.9 to 10.0 months. The combined analysis showed a median overall survival of 13.5 months (95% CI: 10.0–18.2) and a median progression-free survival of 10.1 months (95% CI: 6.3–16.0).
[225Ac]-PSMA therapy is usually well tolerated with manageable haematological and renal toxicities.
In the meta-analysis of Dai et al [19]., xerostomia was the most frequently observed adverse effect, with an estimated proportion of 0.87 (95% CI: 0.63–0.96). Anemia was also commonly reported, with an estimated proportion of 0.75 (95% CI: 0.50–0.90). Severe (Grade 3/4) anemia (0.15, 95% CI: 0.07–0.28) occurred more often than severe xerostomia (0.05, 95% CI: 0.02–0.12), but grade 3-4 adverse events are rare.
Kratochwil et al. reported xerostomia after treatment with an activity of 100 kBq/kg [225Ac]Ac-PSMA-617 or more per cycle [15]. 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 in 347 patients with information on xerostomia, 68% reported it after the first cycle. Bone marrow suppression was also reported with CTCAE grade 3 or above anemia (13%), leukopeina (4%) and thrombocytopenia (7%). Renal toxicity was reported in 5% (grade 3 or above).
All the ligands targeting PSMA and labelled with 225Ac are still in an early investigational phase. [17]