German version

Therapy with Lutetium-177-labeled ligands against the prostate-specific membrane antigen (PSMA) is used to treat PSMA-expressing metastases of castration-resistant prostate cancer. For this purpose, a molecule is used that binds to an enzyme on the cell surface of prostate carcinoma cells, the so-called prostate-specific membrane antigen (PSMA). This molecule is coupled with a radioactive emitter (here: Lutetium-177 = Lu-177) for the therapy. This type of therapy has been offered at our clinic since November 2014.

The radioactive drug (Lutetium-177-labeled prostate-specific membrane antigen ligand) is administered as an infusion into a vein and quickly accumulates in the metastases previously detected by PET/CT (receptor imaging with Ga-68-PSMA or with F-18-PSMA-PET tracers). The tumors/metastases are thus irradiated locally, which is intended to achieve an inhibitory effect on the tumor tissue. The intensity of storage and tumor volume have an influence on the success of the therapy.

A therapeutic Lu-177-PSMA ligand has been approved in 2022 and is now also commercially available in Europe under the trade name PLUVICTO^® following the favorable results of the VISION approval study. It is also possible to employ an analogous compound for therapy which is labeled with Lu-177 directly on site in the Radiopharmacy Department of the University Hospital of Cologne for the purpose of an individual treatment measure in accordance with the German Medicinal Products Act (§ 13 para. 2 AMG). Both treatment options (commercial procurement of PLUVICTO^®, in-house production of a Lu-177-PSMA ligand) are currently used in patient care at the University Hospital of Cologne.

The effectiveness of the therapy concept has been documented by studies (TheraP study and VISION study) and numerous published observational studies. As a rule, it is not a curative therapy option, but one that slows down the progression of the disease or temporarily reduces the tumor burden. To date, this therapy has mostly been offered in an advanced, castration-resistant stage after established lines of therapy have been exhausted, often after pre-treatment with a modern androgen receptor signaling inhibitor and after chemotherapy (e.g. docetaxel). A response to Lu-177-PSMA ligand therapy cannot be guaranteed, but experience to date shows that around 50-60% of patients respond to Lu-177-PSMA ligand therapy.

Lu-177-PSMA ligand therapy should primarily be considered in the third or higher line of therapy if the other established therapy methods have been exhausted, are contraindicated or unsuitable or are not tolerated. This means in concrete terms:

• Under androgen blockade, there is an increase in PSA and the extent of metastases is increasing. At this stage, a so-called castration-resistant, metastasized prostate carcinoma is present.
• After or during drug therapy with abiraterone (Zytiga^®), enzalutamide (Xtandi^®), apalutamide (Erleada^®) or another modern androgen receptor signaling inhibitor, the PSA level has increased.
• First-line chemotherapy with docetaxel has already been given or is not an option (i.e. contraindicated, unsuitable or not tolerated) and second-line chemotherapy is also not an adequate alternative therapy.
• For symptomatic osseous metastases without visceral metastasis and without relevant lymphogenous metastasis, the treatment option of the alpha emitter radium-223 dichloride (Xofigo^®) has been tested.

If the Lu-177-PSMA ligand therapy is well tolerated, 4 to 6 treatment cycles are generally planned at intervals of around 6 weeks. Each treatment cycle is associated with an in-patient stay of around 3 days (guidelines of the Radiation Protection in Medicine Directive). The accumulation of the Lu-177-PSMA ligand in the foci of the disease is recorded by whole-body scintigraphy during each cycle. The response to therapy can be assessed at the end of therapy and, if necessary, during therapy (e.g. if the PSA level rises or the patient's state of health unexplainedly deteriorates) by Ga-68-PSMA PET/CT or an F-18-PSMA PET/CT examination.

The prerequisites and safety instructions for Lu-177-PSMA ligand therapy are checked in advance:

• Proof of PSMA storage of the metastases by Ga-68-PSMA PET/CT or F-18-PSMA PET/CT (if PET/CT is not available by a Tc-labeled PSMA tracer).
• Sufficient bone marrow reserve, demonstrated by peripheral blood count including differential blood count. An interval of at least 6 weeks between the last chemotherapy or Xofigo® must be observed. The bone marrow reserve may be limited by the extent of the bone metastases, by the chemotherapy(ies) or by the previous treatment with Xofigo®.
• Sufficient renal function and exclusion of urinary outflow obstruction, verified by creatinine determination and, if necessary, MAG3 renal scintigraphy. Note: Lu-177-PSMA ligand therapy is possible with an internal ureteral stent or external urinary diversion.
• A sufficiently good general condition, adequate cognitive performance/temporal/spatial orientation ability and control of micturition must be ensured in order to comply with radiation hygiene.

The therapy can therefore not be performed in case of:

• Severe renal insufficiency
• Urodynamically significant urinary retention or urinary outflow restriction
• Bone marrow depression / serious blood count changes
• Uncontrollable urinary incontinence
• Markedly impaired general condition/cognitive impairment or disorientation or other factors that jeopardize compliance with radiation hygiene

Side effects

Like all medicines, PLUVICTO^® or the Lu-177-PSMA ligand can cause side effects, although they will not occur in each patient. Some side effects can be serious. These can be a combination of disease-related damage to individual organs, damage caused by previous therapies (chemotherapy, radiotherapy) and the drug. For example, the therapy can have side effects in the form of suppression of the blood-forming bone marrow (myelosuppression, lack of red or white blood cells, lack of platelets) as well as impairment of kidney function and it contributes to a therapy-related increase in long-term radiation exposure, which has been associated with an increased statistical risk of (secondary) cancer. Additionally, salivary and lacrimal glands also express PSMA and are inevitably irradiated during therapy. This can cause the symptoms of pressure/pain in the salivary glands (salivary gland inflammation), dry mouth, taste disorders, susceptibility to tooth decay and dry eyes. Our patient’s information and the materials from NOVARTIS (as producer of PLUVICTO^®) describe all possible adverse effects in detail.

Measures to reduce the risks of treatment or to treat side effects

- If the number of red blood cells (erythrocytes), platelets (thrombocytes) or white blood cells (leukocytes) is low, a blood transfusion may be necessary. After therapy, the blood count should be checked after 3 and 6 weeks; if necessary in shorter control intervals.

- The therapy can lead to a reduction in kidney function, which is therefore carefully monitored. In the case of pre-existing kidney disease, this may result in permanent dialysis (blood washing). To keep this risk as low as possible, kidney examinations are carried out during the preparatory phase (laboratory, MAG3 kidney scintigraphy) so that the doctor can assess the individual risk. Lu-177-PSMA ligand therapy cannot be carried out in the event of urinary retention. Before administering PLUVICTO^® or the Lu-177-PSMA ligand, you should drink plenty of fluids and urinate as frequently as possible in the first few hours after administration. You should also drink plenty of fluids (approx. 2 liters of water or tea per day) for 2 days after the application of PLUVICTO^® or with the Lu-177-PSMA ligand in order to keep the burden on the kidneys as low as possible (accelerated excretion).

- Shortly before the infusion of PLUVICTO^® or the Lu-177-PSMA ligand, you have the option of cooling your parotid glands with a cooling collar (with a protective intention).