Lutetium-177 PSMA

Lutetium-177 PSMA

Indication Lu-177 PSMA therapy is recommended for patients with metastatic castration-resistant prostate cancer when approved standard treatment options are unavailable or have proven ineffective.

What is Lutetium-177 PSMA Therapy? Lutetium-177 PSMA Therapy is a new approach used in cancer treatment known as Theranostic medicine. in this approach, a tumor-specific drug is used for imaging to detect the tumor and metastases. Subsequently, a tumor-specific drug is used to deliver radiation to these areas. In this way, tumor cells are destroyed more effectively.

Lutetium-177 PSMA therapy is one of the most common methods used in theranostic medicine. In this method, a radioactive substance that binds to the PSMA protein found in prostate cancer cells is used. This radioactive substance focuses on tumor cells, delivers radiation, and causes the cells to die.

The advantages of Lutetium-177 PSMA therapy are:

• It focuses highly on the tumor, and the risk of damage to other tissues is low.

• It provides a long-lasting effect.

• It can be effective even in cancers resistant to other treatments.

The disadvantages of Lutetium-177 PSMA therapy are:

• It may have side effects.

Lutetium-177 PSMA therapy is one of the most effective treatments for metastatic prostate cancer. This treatment can significantly increase patients’ survival time and quality of life.

Lu-177 PSMA: Towards Targeted Therapy

How Does Lutetium-177 PSMA Treat? Lutetium-177 PSMA therapy is a treatment performed using a radioactive substance that binds to a protein called PSMA found in cancerous prostate cells. This radioactive substance focuses on tumor cells, delivers radiation, and causes the cells to die.

What is PSMA? PSMA, also known as glutamate carboxypeptidase II (GCPII), is a type of protein found on the cell membrane of healthy prostate cells. While healthy prostate cells naturally produce very low levels of PSMA, cancerous prostate tumors produce extremely high levels of PSMA. This is also true for metastases of prostate cancer in other parts of the body.

How is Lutetium-177 PSMA Administered? Lutetium-177 PSMA is a treatment administered intravenously. During the treatment, a contrast agent is first given to the patient’s body. This contrast agent allows for better imaging of tumor cells. Then, the Lutetium-177 radioactive substance, attached to a carrier molecule called PSMA, is given intravenously. This radioactive substance binds to the PSMA protein, reaches the tumor cells, and emits radiation.

Efficacy of Lutetium-177 PSMA Therapy Lutetium-177 PSMA therapy is an effective treatment method in metastatic prostate cancer. According to research, approximately half of the patients show a reduction in PSA levels of 50% or more after Lutetium-177 PSMA therapy. Additionally, a partial response in imaging is observed in approximately one-third of the patients.

The most common side effects of Lutetium-177 PSMA therapy are:

• Urinary tract infection

• Dry mouth

• Fatigue

• Headache

• Loss of appetite

• Diarrhea

These side effects are generally mild and do not require discontinuation of treatment.

Who is Lutetium-177 PSMA Therapy Applied To? Lutetium-177 PSMA therapy is applied to patients with metastatic prostate cancer. This treatment is generally preferred in patients who do not respond to other treatments or are resistant to treatment.

How is Lutetium-177 PSMA Therapy Applied in Turkey? Lutetium-177 PSMA therapy is applied in certain hospitals in Turkey. To receive this treatment, the patient must first be evaluated and found suitable by a physician.

Radioactive Elements Used in PSMA Labeling

Radioactive elements used in PSMA therapy are substances that bind to PSMA ligands, focus on tumor cells, and emit radiation causing cell death.

Lutetium – 177 Lutetium-177 (Lu-177) is the most frequently used radioactive element for PSMA therapy in metastatic prostate cancer. It has a half-life of 6.7 days and targets tumor cells with the low beta particles it emits (maximum energy 0.5 MeV).

Actinium-225 Actinium-225 (Ac-225) has a half-life of 10 days and targets tumor cells even more effectively with the alpha particles it emits (maximum energy 6 MeV). However, Ac-225 is a more expensive and less accessible radioactive element compared to Lutetium-177.

Radiopharmaceuticals PSMA ligands are labeled with radioactive elements to become radiopharmaceuticals. Radiopharmaceuticals emit radiation after reaching tumor cells following intravenous administration.

Current clinical knowledge is based on two low molecular weight PSMA-ligands named Lu-177 PSMA-617 and Lu-177 PSMA I&T. These two radioligands possess comparable biodistribution and dosimetric properties.

New Concepts

Some new concepts are being investigated to further improve targeted radioligand therapy for metastatic prostate cancer.

Applications to reduce PSMA uptake in salivary glands and kidneys Salivary glands and kidneys are organs that bind to PSMA ligands at a high rate. This situation can cause unwanted side effects in these organs.

The following methods have been investigated to reduce PSMA uptake in salivary glands:

• Ductal dilation via interventional sialendoscopy, saline irrigation, steroid injection.

• Intraparenchymal injection of Botulinum toxin.

• Externally cooling salivary glands with ice packs.

The following methods have been investigated to reduce PSMA uptake in kidneys:

• Use of 2-PMPA (selective glutamate carboxypeptidase II inhibitor).

• Use of Mannitol.

These methods have not yet been tested in large patient series.

Studies on increasing tumor PSMA uptake via plasma protein binding Increasing the binding of pharmaceuticals to plasma proteins is an effective strategy that improves specific drug uptake while reducing the clearance rate. In light of this information, the use of PSMA radioligands with increased albumin binding and slowed clearance kinetics has been proposed as a promising approach to improve tumoral uptake for therapeutic purposes.

However, parallel to this positive effect on tumoral PSMA uptake, the occurrence of unwanted increased PSMA uptake in healthy organs is a problem that needs to be solved.

Radiohybrid PSMA ligands (rhPSMA) To provide a platform technology allowing for the rapid and efficient labeling of peptide and peptide-like radiopharmaceuticals, a unique and new class of radiopharmaceuticals named radiohybrid PSMA ligands (rhPSMA) has recently been developed.

A unique feature of rhPSMA ligands is that they contain both a covalently bound fluorine and a metal complex. For this purpose, radioactive and non-radioactive isotopes are used interchangeably.

(18F)(natLu)rhPSMA is used for pre-treatment imaging, dosimetry, and evaluation of response to treatment, while (19F)(177Lu) rhPSMA is used in treatment.

How Reliable is Lutetium-177 PSMA Therapy?

Lutetium-177 PSMA therapy is a targeted treatment method used in patients with metastatic prostate cancer. This treatment is performed using a radioactive substance that binds to a protein called PSMA. The radioactive substance focuses on tumor cells, emits radiation, and causes the cells to die.

The safety of Lutetium-177 PSMA therapy has been evaluated in various observational studies. In these studies, the treatment was seen to be generally safe and to have an acceptable side effect profile.

Common Side Effects The most common side effects of Lutetium-177 PSMA therapy are:

• Dry mouth: Grade 1 dry mouth is seen in approximately 87% of patients.

• Nausea and vomiting: Grade 1 or 2 transient nausea is seen in approximately 50% of patients, and Grade 1 or 2 vomiting in 20%.

• Fatigue: Grade 1 or 2 fatigue is seen in approximately 50% of patients.

Other Side Effects Other possible side effects of Lutetium-177 PSMA therapy are:

• Hematological toxicity: Grade 3 or 4 hematotoxicity is seen in approximately 10% of patients. This manifests as a decrease in the number of blood cells.

• Renal dysfunction: Grade 3 or 4 renal dysfunction is seen in approximately 5% of patients.

• Salivary gland dysfunction: Grade 3 or 4 salivary gland dysfunction is seen in approximately 5% of patients.

Rarer Side Effects Rarer side effects of Lutetium-177 PSMA therapy are:

• Neurological toxicity: Grade 3 or 4 neurological toxicity is seen in approximately 1% of patients. This may manifest with symptoms such as headache, dizziness, seizures, and paralysis.

• Liver dysfunction: Grade 3 or 4 liver dysfunction is seen in approximately 1% of patients.

• Pancreatic inflammation: Pancreatitis is seen in approximately 1% of patients.

Nephrotoxicity

NS: Within Normal Limits / WNL, N: Normal

Xerostomia (Dry Mouth)

Hematotoxicity / Bone Marrow Toxicity

WNL: Within Normal Limits, N: Normal *units of transfusion

Interaction with Other Medicinal Products in Lutetium-177 PSMA Therapy

Radiation Safety Various studies provide data on external radiation exposure, excretion, and effective half-life from patients who have undergone Lu-177 PSMA therapy. In cases where patients are discharged at least 48 hours after treatment administration, the maximum effective dose level for members of the public per treatment is approximately 139 ± 53 μSv. However, these data cannot be easily converted to outpatient treatment applications. In day-case treatment applications where patients are discharged 6 hours after administration, the effective dose is 202 ± 43 μSv.

Regarding personnel and post-discharge precautions, the same precautions recommended for PRRT with Lu-177 in neuroendocrine tumors should be taken.

Who is Lutetium-177 PSMA Therapy Applied To?

Lutetium-177 PSMA therapy is a targeted treatment method applied in patients with metastatic, castration-resistant prostate cancer (mCRPC). In this treatment, a radioactive substance binding to a protein called PSMA is used. PSMA is highly expressed in prostate cancer cells. Therefore, the PSMA ligand binds to tumor cells, causing radiation to accumulate in the tumor cells. This leads to the death of tumor cells.

Indications for Lutetium-177 PSMA therapy are:

• When other treatment options are exhausted: Lutetium-177 PSMA therapy can be used when other treatment options are ineffective or can no longer be applied. This may be due to the deterioration of the patient’s general health, impairment of organ functions, or progression of the disease despite treatment.

• In patients where standard alternative treatment options are not suitable: Lutetium-177 PSMA therapy can also be used in some patients where standard alternative treatment options are not appropriate. For example, in patients with bone metastases, chemotherapy may be difficult to administer due to the risk of bone marrow toxicity. In this case, Lutetium-177 PSMA therapy may be preferred as it causes less bone marrow toxicity.

• In cases where sufficient PSMA ligand uptake is shown in pre-treatment Ga-68 PSMA PET/CT imaging: The efficacy of Lutetium-177 PSMA therapy depends on the PSMA uptake shown in pre-treatment Ga-68 PSMA PET/CT imaging. Ga-68 PSMA PET/CT imaging is a highly effective method for demonstrating PSMA expression in tumor cells. Therefore, pre-treatment Ga-68 PSMA PET/CT imaging is important for assessing the suitability of Lutetium-177 PSMA therapy.

Contraindications for Lutetium-177 PSMA therapy are:

• Cases with a life expectancy of less than 6 months (ECOG performance score >2): Lutetium-177 PSMA therapy, like other radionuclide therapies, is not recommended in patients with short life expectancy. This is due to the limited contribution of the treatment to efficacy and the patient’s quality of life.

• In the presence of unmanageable urinary tract obstruction or hydronephrosis: Lutetium-177 PSMA therapy can increase radiation exposure to the kidneys. Therefore, in the presence of unmanageable urinary tract obstruction or hydronephrosis, this condition must be corrected before treatment.

• In case of progressive deterioration in organ functions: Lutetium-177 PSMA therapy can increase radiation exposure to organs such as kidneys, liver, and bone marrow. Therefore, in patients with progressive deterioration in organ functions, the risks and benefits of the treatment should be carefully evaluated.

• In bone marrow depression: Lutetium-177 PSMA therapy can cause bone marrow toxicity. Therefore, in patients with bone marrow depression, the risks and benefits of the treatment should be carefully evaluated.

Lutetium-177 PSMA therapy has no known interaction with other medicinal products. However, due to its well-known effects on bone marrow suppression, treatment with hemibody irradiation (or equivalent), chemotherapy, or radioactive bone agents (Radium 223) should be discontinued at least 4 weeks prior.

Dosimetry in Lutetium-177 PSMA Therapy

Specific absorbed dose tolerance limits determined for normal organs in Lutetium-177 PSMA therapy are:

• For red bone marrow: 2 Gy

• For kidneys: 28-40 Gy

• For salivary glands: 35 Gy

Lutetium-177 PSMA therapy falls into the non-standard category, especially when individual dosimetry is applied. Most national regulations now require the inclusion of a medical physicist with specialized training in this process. In cases where patients cannot tolerate the multiple serial imaging required for dosimetry, simplified methodologies may be preferred. Dosimetry evaluations can also be performed after a treatment cycle to verify the efficacy of future applications. However, in subsequent cycles, doses absorbed by the tumor may be lower due to the therapeutic effect of the initial cycle(s). Conversely, physiological PSMA uptakes in normal organs are not significantly affected by treatment cycles.

For optimal dosimetry, sequential imaging should preferably be performed at several time points using quantitative three-dimensional techniques such as SPECT/CT. Since late-phase imaging largely determines the doses absorbed by organs or tumoral tissues, scans should preferably be performed at least 4-7 days after administration. For organ-based dosimetry purposes, each organ mass of the patients should be determined for dose-limiting organs.

The minimum standard should be dosimetry calculation based on three-dimensional quantitative techniques at a single imaging time point—preferably at least three days after administration. For organ-based dosimetry, each patient’s organ masses should be determined, and effective half-lives should be stated.

In cases where dosimetry is not performed, a rough estimate of the absorbed dose coefficient in kidneys and salivary glands can be made with average values given in guidelines. However, these values are valid only in normal pharmacokinetic behavior; when renal function is impaired, the dose absorbed by organs (especially in red bone marrow in the presence of PSMA-expressing bone lesions) can increase significantly. Therefore, this approach is not sufficient to predict treatment-related toxicity in each patient, and close monitoring is recommended to assess toxicity.

When possible, separate tumor/normal organ dosimetry should be reported according to EANM guidelines.

Estimated absorbed dose coefficients for critical organs:

• For Kidney: 0.5±0.2 (Gy/GBq ± SD)

• For Salivary glands: 0.8±0.5 (Gy/GBq ± SD)

Preparation Before Lutetium-177 PSMA-Radioligand Therapy

Lutetium-177 PSMA-radioligand therapy is a targeted treatment method applied in patients with metastatic, castration-resistant prostate cancer (mCRPC). Before this treatment, some preparations must be made to evaluate the patient’s suitability for treatment.

When the patient first applies to the Nuclear Medicine Clinic, they must bring the following information and documents:

• Most current epicrises (medical reports) related to prostate cancer

• Pathology results

• Blood tests

• Whole-body bone scintigraphy, CT, MRI, and Ga-68 PSMA PET/CT reports

Blood tests Blood tests are important for evaluating the patient’s general health status and suitability for treatment. These tests may include:

• PSA

• Complete blood count

• Serum electrolytes (sodium, potassium, phosphate)

• Renal function tests (urea, creatinine, alkaline phosphatase)

• Liver function tests (albumin, AST, ALT, LDH, bilirubin)

• Bone marrow function tests (total protein, 24-hour urine creatinine clearance)

Whole-body bone scintigraphy, CT, MRI, and Ga-68 PSMA PET/CT reports These imaging tests are used to evaluate the spread of cancer. Ga-68 PSMA PET/CT is an imaging method showing the PSMA protein, which is highly expressed in prostate cancer cells. This method is one of the most accurate methods for evaluating the spread and activity of cancer.

Preparation before Lutetium-177 PSMA-radioligand therapy is important for evaluating the patient’s suitability for treatment and reducing potential risks. Therefore, it is important for patients to complete all necessary preparations before treatment.

How is Lutetium-177 PSMA-Radioligand Therapy Administered?

Treatment Regimens Various treatment regimens are available for Lutetium-177 PSMA-radioligand therapy. These regimens may vary depending on the type of ligand used, the patient’s general health status, and response to treatment.

Generally, the following regimens are applied in Lutetium-177 PSMA-radioligand therapy:

• Activity administered per treatment: It is between 3.7-9.3 GBq (100–250 mCi). Current phase II studies support standard activities of 6-8.5 GBq (160-230 mCi) in most cases. An ongoing phase III study (VISION) applies a standard activity of 7.4 GBq (200 mCi) in a total of 4 to 6 cycles at 6-week intervals.

• Time interval between cycles: 6-8 weeks.

• Number of cycles: Between 2 and 6 (varies depending on response, prognosis, and renal risk factors).

• Renal toxicity risk: In patients with a life expectancy of more than 1 year, the cumulative dose absorbed by the kidney should not exceed 40 Gy per patient. However, in cases where the dose absorbed by the kidneys is close to or higher than this limit, the risk/benefit ratio must be evaluated for each patient. The maximum cumulative absorbed dose should be spread over the longest clinically possible period.

• Evaluation of response to treatment: It should be evaluated in every cycle with PSA and post-treatment scintigraphic imaging. Additionally, additional staging studies should be performed with cross-sectional imaging, preferably PSMA PET/CT, every two cycles.

Premedication for Lutetium-177 PSMA Therapy In Lutetium-177 PSMA therapy, there is no need for any premedication. Most patients tolerate the treatment well. However, the following precautions may need to be taken in some patients:

• Diuretics may be used after administration to support the clearance of unbound Lutetium-177 PSMA.

• Application of cold packs to salivary glands during the “blood pool phase” may reduce the uptake of Lutetium-177 PSMA in salivary glands.

• It is required to use oral corticosteroids (e.g., 20 mg/day Prednisolone) starting 1 day before Lu-177 PSMA administration for a duration of 1-2 weeks.

Administration of Lutetium-177 PSMA Therapy Lutetium-177 PSMA therapy is administered in the nuclear medicine clinic. The treatment is performed following a preparation period lasting 3-5 days.

• Preparation Process: Before treatment, the patient’s general health status and suitability for treatment are evaluated. For this purpose, complete blood count, kidney, liver, and bone marrow function tests are performed. Also, Ga-68 PSMA PET/CT imaging is performed to evaluate the patient’s response to treatment.

• Treatment: The treatment is given to the patient intravenously. The treatment duration varies according to the type of ligand used. For example, for Lutetium-177 PSMA-167 ligand, the treatment duration is approximately 45 minutes.

• Post-Treatment: The patient needs to be monitored closely. For this purpose, PSA level, kidney and bone marrow function tests, and Ga-68 PSMA PET/CT imaging are performed.

Post-Treatment Scanning After Lu-177 PSMA administration, at least 1 whole-body scan, preferably SPECT(/CT), should be performed between the 4th and 48th hours. For this purpose; medium energy, general-purpose, parallel-hole collimators with energy peaks of 113 KeV (20% window width) and 208 KeV (15% window width) should be used.

Combination of PSMA Therapy with Other Treatment Options Combination of Lu-177 PSMA therapy with chemotherapy is not recommended. Also, there is no data regarding the combination of both treatments in patients who still respond to new-generation hormone therapies (abirateron/enzalutamide). However, in patients with brain metastases, Lu-177 PSMA therapy can be combined with external radiotherapy of brain metastases. Furthermore, individual experiences have shown that the combination of PSMA therapy with external radiotherapy is possible and safe in patients with painful bone metastases or risk of fracture.

Follow-up After Lutetium-177 PSMA Therapy

To evaluate the efficacy and safety of this treatment, patients must be closely monitored before, during, and after treatment.

Follow-up During Treatment During treatment, the patient should be monitored for the following symptoms:

• Nausea

• Vomiting

• Loss of appetite

• Gingivitis

• Kidney pain

• Blood in urine

If any of these symptoms occur, the patient needs to consult their doctor.

Post-Treatment Follow-up After treatment, the patient needs to be monitored with the following tests:

• Complete blood count: Should be checked every 2-3 weeks (depending on baseline status), up to 12 weeks after each cycle.

• PSA as a tumor marker: Should be followed up at 4-week intervals. PCWG3 (Prostate Cancer Clinical Trials Working Group 3) criteria should be considered in follow-up and interpretation.

• Basic liver and kidney profile: Should be evaluated every 6-8 weeks.

• Physical examination: Should be performed before every treatment.

• Post-treatment screening scintigraphy (4-48 hours after administration): Confirms the uptake of Lu-177 PSMA in lesions and, when performed at later time points, serves to image the response of PSMA-positive lesions to treatment.

Imaging-Based Re-staging Follow-up examinations to be performed after several cycles of Lu-177 PSMA therapy: Imaging-based re-staging allows for the detection of PSMA-negative lesions. For this purpose, CT and MRI images that are an integral part of existing PSMA PET/CT or PET/MRI examinations, whole-body bone scintigraphy, or FDG PET/CT imaging can be used. The frequency of re-staging with imaging can be adjusted according to the reliability of post-treatment scans and PSA response. Performing imaging every 2-3 cycles according to PCWG3 criteria would also be reasonable for this purpose.

Re-treatment Lu-177 PSMA treatment duration is planned according to individual clinical needs, carefully evaluating the cumulative absorbed doses of salivary glands and kidneys. Blood count, general medical condition, and inclusion/exclusion criteria should be re-evaluated before re-treatment. Repeated Lu-177 PSMA therapy has been applied up to a total of seven cycles in current observational studies without excessive toxicity. Treatment repeated every 6-8 weeks allows for recovery of hematotoxicity in most cases and is consistent with published protocols.

Conclusion Lutetium-177 PSMA therapy is a treatment method that can provide significant benefits in patients with metastatic prostate cancer (mCRPC). To evaluate the efficacy and safety of this treatment, patients must be closely monitored before, during, and after treatment.

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