Lu-177-PSMA therapy for metastasized prostate cancer

At the Department of Nuclear Medicine of LMU Munich, the so-called radio-ligand therapy (RLT) with Lutetium-177 (Lu-177) marked PSMA antagonists is offered for patients with metastasized prostate cancer. The therapy is an individualized treatment. It is the application of an effective, but not yet an approved, therapy for individual cases. It may be applied in patients with progressive and otherwise untreatable diseases. However this individualized treatment has so far no proven benefit in rigorosly controlled prospective studies. Therefore it differs from therapies which are proven state of the medical art in that risks and side-effects are not fully known. In case of Lu-177 PSMA therapy, the scientific findings to date show very good results with acceptable side-effects [1, 2]. The therapy is offered to patients with metastasized prostate cancer, with disease progression despite hormone therapy or chemotherapy. In contrast to Xofigo therapy (Ra-223), patients with metastases outside the skeletal system (e.g. soft tissue or lymph node metastases) can be treated.

In advanced stages we offer on an individual basis also the possibility of an Actinium-225 (AC-225) PSMA treatment.

Therapy mode of action

Generally, cancerous cells from the prostate bear the prostate specific membrane antigen (PSMA) on the cell surface. This membrane antigen serves as a target for certain peptides, so-called PSMA ligands (PSMA-DKFZ-617), which can been radiolabeled with the therapeutically effective beta emitter Lu-177 (Lu-177-PSMA-DKFZ-617). A schematic illustration of a PSMA ligand, radiolabeld with Lu-177 is shown in illustration 1.

Since the protein molecule specifically binds to PSMA on the tumor cells, the therapy substance accumulates in the tumor after injection. The therapy substance is delivered to the tumor tissue via the bloodstream and leads to a targeted irradiation of the malignant cells (cf. illustration 2). Thereby, the radioactive irradiation in the normal tissue only reaches over a few millimeters. Thus RLT can generate a higher and more effective radiation dose to cancer cells than external radiation therapy.

Various clinical studies show that RLT reduces tumor growth or sunstanially decreases tumor volume in the majority of these advanced cases. The therapy can also reduce pain and PSA values and improve the quality life quality.

Illustration 3 shows a patient with good response to 4 cycles of Lu-177 PSMA therapy.

Preconditions prior to Lu-177 PSMA therapy

Lu-177 PSMA therapy is available for patients with tumors with sufficient PSMA uptake that are progressing under approved treatment options (hormone therapy, external radiation therapy or chemotherapy). Before Lu-177-PSMA-DKFZ-617 therapy can be performed, PSMA uptake and the indication to implement the therapy must be visualized by PSMA PET/CT (standard procedure at our department). In addition to further requirements which the treating doctors will individually review prior to a Lu-177 PSMA therapy, renal function and bone marrow function must be within certain limits. As a rule, further tests (e.g. kidney function scintigraphy, laboratory tests and others) are needed, which all can be performed at our deparment.

How is the therapy performed?

Therapy is performed on an in-patient basis at our therapy ward K0. The therapy itself takes approximately 15 minutes (infusion). Due to the non-target uptake of Lu-177 PSMA in the salivary glands, the patients should apply cold packs 30 minutes prior to and up to 4 hours after therapy, to cool the salivary glands and thus reduce blood circulation. Thus, a lesser concentration of radioactivity in the salivary glands is expected. To prevent damage to the kidneys, i.v. infusions will be given directly before, during and after therapy. Moreover, on the day of therapy and the days after, sufficient uptake of liquid is recommended to reduce radiation dose to the kidneys and the body. The therapy generally requires a 4 day hospitalization.

After therapy, the therapy unit may not be left for 48 hours. After discharge, laboratory control of the blood, liver and kidney values after approx. 2 and 6 weeks is required. This can be done at home by the GP, urologist or oncologist.

Generally, no less than 2 therapy cycles (usually 4) in a 8 week interval will be performed. To review the therapy response as well as side-effects and complications, follow-ups in regular time intervals (e.g. PET/CT, kidney scintigraphy) will be performed. In case of good response or stabilization of the disease and further good storage in PSMA ligand PET/CT, further therapy cycles can be performed in case of good bone marrow and kidney function.

Complications and side-effects of therapy

The results to date show that no relevant severe acute complications are observed. However, despite diligent care, the Lu-177 PSMA therapy may entail side-effects and complications. Since the therapy is an individualized treatment with an unapproved drug, formerly unknown risks, side-effects and complications cannot be totally excluded.

The following side-effects and complications are presently known:

General side-effects and complications:

• Fever after therapy
• Theoretically, allergic reactions during administration of the therapy substance, up to an allergic shock, might occur (however, this has never been observed for this therapy)
• Nausea, vomiting and lack of appetite
• Sometimes slight loss of hair during the weeks after therapy
• Rare cases report change of taste after RLT has been reported
• Tiredness and fatigue (up to a few weeks after RLT)

Specific side-effects and complications:

• The number of red blood corpuscles (erythrocytes), blood platelets (thrombocytes) and white blood corpuscles (leucocytes) may be reduced after therapy. Therefore, the hemogram must be controlled 2 and 6 weeks after therapy. In individual cases, repeated therapies may entail a long-term, in rare cases life-threatening, limitation of the bone-marrow function, necessitating blood transfusions.
• Repeated therapies may entail a limitation of the kidney function which is why it is reviewed prior to each therapy. In individual cases, repeated therapies may entail a permanent loss of the kidney function, necessitating external blood washing (dialysis). This is avoided by individualized dosimetry at each cycle and repeated kidney function tests.
• Repeated therapies may reduce the saliva production, causing dry mouth. This may increase caries. Change of taste may also be caused thereby.
• In very rare cases, the first 72 h after therapy may lead to symptoms of incarceration in the spinal marrow, since large extensive metastases can swell temporarily.
• Any radiation entails the risk of secondary malign tumors, however, if at all they will occur at a delay of years or decades.
• Since there is no long-term experience, long term side-effects may occur that are so far unknown.

Important behavior for patient:

• On the day of therapy, several liters of liquid should to be drunk, to keep the dose to the kidneys and the radiation load of the remaining body as low as possible (accelerated excretion).
• The salivary glands should be cooled by cold packs approx. 30 minutes prior to and up to 4 hours after therapy to thus reduce the blood flow. This should lower the concentration of radio-activity in the salivary glands.
• During the in-patient stay, you are unfortunately not allowed any visitors on the therapy unit K0. Only in exceptional cases and after prior consultation with your doctor you can be allowed to leave the unit during the first 48 h after therapy.
• After discharge, your relatives do not have to fear any dangerous radiation risk.
• Please immediately inform your doctor if you experience any symptoms, irrelevant of kind and graveness.