Lu-177 PSMA therapy is indicated in patients with prostate cancer resistant to metastatic castration, when approved standard treatment methods are inadequate or not suitable.

What is Lutetium-177 PSMA Therapy ?

Theranostic is an emerging field in the medical world. It is an approach in which tumor and metastases detected by imaging with a tumor-specific drug and they can be treated with a same specific drug, which is previously known, how far it will go, and how its power will affect the diseased tissue. This approach enables the transition from traditional medicine to contemporary personal medicine practices. In prostate cancer, on the one hand, with Ga-68 PSMA PET / CT, tumoral tissues of prostate cancer can be displayed with high sensitivity and specificity, on the other hand, specific and targeted treatment of these tumoral tissues can be performed with Lu-177 PSMA. This is a very successful and new method for theranostic applications.

The first PSMA targeted Lu-177 PSMA therapy was successfully realized in April 2013 in Bad Berka-Germany. This is the first theranostic PSMA targeted compound; PSMA was called I&T (“imaging and therapy”) and this ligand was later used for both imaging with Ga-68 and radioligand treatment with 177Lu in many centers.

How Lutetium-177 PSMA Treats ?

PSMA, also known as glutamate carboxypeptidase II (GCPII) with multiple cellular functions, is a type of protein found in healthy prostate cell membranes. Although healthy prostate cells naturally produce very low levels of PSMA, cancerous prostate tumors produce extremely high levels of PSMA (usually 1000 times higher than normal prostate cells). This is also valid for prostate cancer metastases in other parts of the body. The 177Lu atom is a radioactive element emitting radioactive beta particles that can be attached to a carrier molecule called PSMA. When Lu-177 PSMA is administered intravenously, it goes to all tumor tissues where PSMA is present and destroys these cancer cells by emitting radiation. Since Lu-177 PSMA therapy targets cancer tissue, the radiation dose received in other parts of the body is very low. The part of Lu-177 PSMA that is not retained by tumor cells passes into saliva, urine and feces and is excreted from the body.

Lu-177 PSMA therapy is performed after the evaluations of a multidisciplinary team.

 Lu-177 PSMA therapy has been developed in non-commercial, academic, research settings in the US and Europe. More recently, it has entered clinical practice with the courage and efforts of physicians, and of course to treat their patients suffering from incurable, fatal disease. This is a similar process to the peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors introduced in some European countries in the mid-1990s. However, even a proven therapy like PRRT took more than 15 years to obtain EMA and FDA approvals. Dosimetry and initial results are similarly promising for Lu-177 PSMA therapy.

Although there is an ongoing phase 3 study (VISION) evaluating the efficacy of Lu-177 PSMA therapy in metastatic CRPC (mCRPC) patients, PSMA therapy is currently only an experimental treatment approach recommended by the guidelines for mCRPC, followed by currently approved treatments.

Approved treatments for prostate cancer; They are first and second-line chemotherapies using docetaxel and cabazitaxel, which frequently cause side effects but can prolong overall survival by only a few months with new generation hormone therapies using abiraterone and enzalutamide (median survival prolonging up to 3.9 months and 4.8 months, respectively).

In addition, 223 Radium-chloride, which targets only diffuse or painful osteoblastic bone metastases and does not treat nodal or visceral metastases, increases median overall survival by 3.6 months. 223 Radium therapy should be used as third-line therapy in patients with multiple painful bone metastases without any visceral or lymph node metastases.

In some patients for whom chemotherapy is contraindicated, Lu-177 PSMA therapy may be used after abiraterone / enzalutamide.

Treatment Effectiveness

As a tumor marker, PSA is one of the most frequently used parameters in different prostate cancer treatments to evaluate response to treatment. The efficacy after Lu-177 PSMA treatment has been evaluated by various meta-analyzes and observational studies. After Lu-177 PSMA treatment, the biochemical response, defined as a 50% or more reduction in PSA, is observed in more than half of the patients. More than one third of the patients also had a partial response on imaging. In a recent phase II study, 57% of patients demonstrated a 50% or greater reduction in PSA. Objective response in nodal or visceral disease was also reported by imaging in 82% of patients with measurable disease. The available data indicate that there is no difference in efficacy between Lu-177 PSMA-617 and Lu-177 PSMA I&T ligands. Visceral metastasis and serum alkaline phosphatase ≥ 220 U / L were found to be associated with poor prognosis. In small observational studies, more than half of the patients showed significant improvement in pain and quality of life.

There are still few published studies on Ac-225 PSMA, which was used for the first time in humans in 2016. A higher rate of dry mouth is also reported with a higher response rate in Ac-225 PSMA. In order to deal with this side effect, tandem treatment protocols using Ac-225 PSMA and Lu-177 PSMA are being studied.

Radioactive Elements Used in PSMA Labeling

Lutetium-177 (Lu-177) is a radioactive element that emits gamma and beta radiation, with a half-life of 6.7 days. The average distance traveled by low beta particles (maximum energy 0.5 MeV) is 0.7 mm, and the maximum distance traveled in soft tissue is 2.1 mm. The energy peaks with gamma emissions used in post-treatment imaging are 112.9 keV and 208.4 keV. 177 Lutetium is the most commonly used radioactive element for PSMA therapy worldwide, and the majority of PSMA therapy data published is based on treatments using the Lu-177 PSMA-617 and Lu-167 I & T ligands.

Actinium-225 (Ac-225) is the second most frequently used radioactive element for PSMA therapy, with a half-life of 10 days and an alpha particle with 6 MeV energy. Ac-225 PSMA targeted alpha therapy enables a more convenient microdosimetry in the presence of red bone marrow infiltration as an alpha particle has a much shorter tissue penetration range than the beta particle. This may be a good choice for patients presenting with a “superscan” pattern in their imaging. In addition, in case of resistance to Lu-177 PSMA treatment, Ac-225 PSMA-targeted alpha therapy was also performed as an additional step.


Lu-177 PSMA ligands represent medicinal products and may be used in certain cases without official approval, taking into account national regulations. In terms of preparation and quality control (QC), recommendations of the common IAEA, EANM and SNMMI practice guidelines regarding the use of PRRT in neuroendocrine tumors should be considered. In line with this guideline, the radiochemical impurity from free Lu-177 should be less than 2% and quality control should include both high performance liquid chromatography and instant thin layer chromatography methods.

The available clinical information is mainly based on two low molecular weight PSMA-ligands, namely Lu-177 PSMA-617 and Lu-177 PSMA I&T. These two radioligands, radiolabeled with 177Lu, which emit beta particles, have comparable biodistribution and therefore dosimetric properties. Therefore, both ligands can be applied interchangeably. The development of second generation ligands is still continuing.

New Concepts

Some new concepts are being explored to further improve targeted radioligand therapy of metastatic prostate cancer.

Applications to reduce Lu177 PSMA involvement in salivary glands and kidneys

Although the following solutions have been pursued to reduce the radiation dose in the salivary glands and kidneys, limited success has been achieved:

For the salivary glands;

– Canal enlargement with interventional sialendoscopy, saline irrigation, steroid injection

– Intraparenchymal injection of botulinum toxin

– Cooling the salivary glands from the outside with ice bags

For kidneys;

Although 2-PMPA (selective glutamate carboxypeptidase II inhibitor) and mannitol usage have been investigated, none of these methods have been applied to a large patient series. None of these experimental approaches can be recommended for routine practice today, as each additional intervention increases the risk of complications or may produce its own side effects.

Studies to increase tumor PSMA uptake by binding to plasma proteins

Increasing the binding of pharmaceuticals to plasma proteins can be an effective strategy that decreases clearance while improving specific drug retention. 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 therapeutic tumor involvement. However, parallel to this positive effect in tumoral PSMA uptake, unwanted increased PSMA uptake in healthy organs is a problem that needs to be solved.

Radiohybrid PSMA ligands (rhPSMA)

A unique new class of radiopharmaceuticals, called radiohybrid PSMA ligands (rhPSMA), has recently been developed to provide a platform technology that allows for fast and efficient labeling of peptide and peptide-like radiopharmaceuticals such as PSMA labeled with 18F or radiometals. A unique feature of rhPSMA ligands is that these ligands contain both fluorine and metal complexes covalently linked. For this purpose, radioactive and non-radioactive isotopes are used alternately (eg [19F] [177Lu] rhPSMA and [18F] [natLu] rhPSMA). Two chemically identical ligands [18F] [natLu] rhPSMA are used in pretreatment imaging, dosimetry and evaluation of treatment response, while its twin [19F] [177Lu] rhPSMA is used in therapy.

Is Lutetium-177 PSMA Therapy Safe ?

A safety profile suitable for Lu-177 PSMA therapy is available.

Safety of Lu-177 PSMA therapy has been reported as part of several observational studies. In these studies, grade 3-4 hematotoxicity appears to occur in less than 10% of patients. Baseline low blood count levels and widespread bone marrow involvement have been associated with severe haematotoxicity in individual patients. However, the rate of grade 3-4 adverse events is less than 5% for all other categories, including salivary gland function. First degree dry mouth can be seen in 87% of the patients, first or second degree transient nausea in 50%, and 1st or 2nd degree fatigue in 50%. The most common toxic effects that may be associated with Lu-177 PSMA-617 were reported as 37% grade 3 lymphocytopenia, 13% grade 3 anemia, and 13% grade 3 or 4 thrombocytopenia. In summary, the data show a suitable safety profile for Lu-177 PSMA therapy.














NS: normal limit, N normal

Xerostomia (Dry mouth) 

1st Degree

Symptomatic, but no need for serious dietary changes (eg. dry or dense saliva); unstimulated saliva flow is > 0.2 mL / min.

2nd Degree

Moderate symptoms; have oral intake changes (eg. plenty of water, other lubricants are needed. Diet restricted to purees and / or soft, juicy foods); unstimulated saliva flow is 0.1-0.2 mL / min.

3rd Degree

There is not enough nutrition orally. Tube or parenteral nutrition is required; unstimulated saliva flow is <0.1 mL / min.

 Hematotoxicity / Bone marrow toxicity 










































age threat




gross 1-2*

gross 3-4*


NL: normal limit, N normal

* unit transfusion

Interaction with Other Medicinals

No clinical interaction studies have been conducted. Treatment with half-body irradiation (or equivalent), chemotherapy, or radioactive bone agents (Radium 223) should be discontinued at least 4 weeks in advance because of their well-known effects on bone marrow suppression.


Specific absorbed dose tolerance limits for normal organs in the treatment of Lu-177 PSMA;

  • For red bone marrow 2 Gy (single exposure)
  • For kidneys 28-40 Gy
  • For salivary glands 35 Gy’dir.

Lu-177 PSMA therapy falls into the non-standard category, especially when individual dosimetry is applied, and most national regulations now require a specialist trained medical physicist to be involved in this process. In cases where patients cannot tolerate multiple serial imaging required for dosimetry, simplified methodologies may be preferred. Dosimetry evaluations can also be done after a course of treatment to confirm the effectiveness of future applications. However, the doses absorbed by the tumor in subsequent cycles may be lower with the therapeutic effect of the initial cycle (s). However, physiological PSMA uptake in normal organs is not significantly affected by treatment cures.

  • For optimal dosimetry, sequential imaging should be performed at several time points, preferably using quantitative three-dimensional techniques such as SPECT / CT. Since imaging in the late period largely determines the absorbed dose of organs or tumoral tissues, screenings should preferably be performed at least 4-7 days after the application. Organ-based dosimetry purposes for dose-limited organs, the individual organ mass of the patients should be determined.
  • 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, organ masses of each patient should be determined and their effective half-lives specified.
  • In the absence of dosimetry, a rough estimate of the dose coefficient absorbed in the kidneys and salivary glands can be made with the mean values given in the guidelines. However, these values are valid only in normal pharmacokinetic behavior. When renal function is impaired, the dose absorbed by the organs (especially in the red bone marrow in the presence of PSMA expressing bone lesions) may also be significantly increased. Therefore, this approach is not sufficient to predict treatment-related toxicity in each patient, and close follow-up is recommended to assess toxicity.
  • Whenever possible, individual tumor / normal organ dosimetry should be reported according to EANM guidelines.

Estimated absorbed dose coefficients for critical organs :

  • For kidneys 0.5±0.2 (Gy/GBq ± SD)
  • For salivary glands 0.8±0.5 (Gy/GBq ± SD)

 Radiation Safety

Various studies, from patients treated with Lu-177 PSMA; provides data on external radiation exposure, excretion, and effective half-life. When patients are discharged at least 48 hours after treatment, the maximum effective dose level of community members per treatment is approximately 139 ± 53 μSv. However, these data cannot be easily converted into outpatient practices. Patients are discharged 6 hours after the application, and the effective dose is 202 ± 43 μSv in daily treatment applications.

With regard to staffing and post-discharge measures, the same precautions as recommended for PRRT with Lu-177 in neuroendocrine tumors should be taken.

Who is Lutetium-177 PSMA Treatment Applied ?


Lu-177 PSMA therapy; In patients with metastatic castration-resistant prostate cancer (mCRPC), they may be recommended by their referring physician for treatment in the following situations :

  • When there are no possible treatment options left
  • In patients for whom standard alternative treatment options are not suitable
  • When sufficient PSMA ligand uptake is shown before treatment with Ga-68 PSMA PET/CT imaging,

Detection of diseased foci (lesions) with Ga-68 PSMA PET / CT imaging can be performed with high success. Until now, no consensus has been reached on Ga-68-PSMA-PET/CT imaging on what amount of PSMA uptake in the lesion would be sufficient for treatment. However, based on experience with other theranostic agents such as DOTA-TOC and DOTA-TATE, it can be said that “adequate uptake” is at least the higher level of PSMA uptake in normal organs, such as the liver. In PSMA treatments, pre-treatment Ga-68 PSMA PET/CT imaging, in the areas of dominant tumor uptake, the PSMA maximum SUV value should be at least 1.5 times the average liver SUV value and there should be no active tumor tissue that does not show PSMA uptake. For this purpose, FDG PET/CT imaging should be performed to exclude patients with active disease that do not express PSMA.

In addition, Lu-177 PSMA treatment should not be applied in cases where liver metastasis without PSMA uptake is detected in Ga-68 PSMA PET/CT imaging before treatment, even if all other lesions show very high PSMA expression. Therefore, the final decision should be based on clinical findings and careful consideration of imaging findings.

The decision as to whether a patient is suitable for a particular alternative therapy is often beyond the expertise of the Nuclear Medicine Physician. In terms of androgen deprivation therapy (LHRH analogues / antagonists and first generation antiandrogens), secondary hormone manipulations (abiraterone, enzalutamide), chemotherapy or Radium-223 radionuclide therapy, an uro-/oncologist is required. It should be a standard approach to evaluate the treatment decision in the multidisciplinary tumor council including uro-/oncology, Nuclear Medicine and Radiation Oncology, and the individual indication for Lu-177 PSMA therapy should be decided in this multidisciplinary tumor council.

Patients’ right to self-determination must be respected and patients should not be forced to accept these recommendations. In any case, it should be documented that the patient is informed about the potential risks and benefits of the treatment options by an expert in the relevant field (eg uro-/oncologist).


  • Similar to other radionuclide treatments, cases with a life expectancy of less than 6 months (ECOG performance score >2); unless the main goal is to suffer from symptoms associated with the disease
  • In the presence of unmanageable urinary tract obstruction or hydronephrosis

In cases with this diagnosis or high urinary retention, 99mTc-MAG3 or 99mTc-DTPA renal scintigraphy should be performed before the first course of Lu-177 PSMA therapy. If obstruction is detected, it should be treated first. Renal scintigraphy before subsequent courses is optional depending on the renal functions and the first kidney scintigraphy results.

  • In case of progressive deterioration in organ functions

– GFR <30 mL / min and / or creatinine value> 2 times above upper limit of normal (However, Lu-177 PSMA treatment can be applied to dialysis-dependent patients..)

– Liver enzyme levels> 5 times above the upper limit of normal (In patients with liver metastases, liver parameters may be elevated, this alone is not a contraindication to Lu-177 PSMA therapy. However, in patients with high bilirubin levels, cholestasis should be ruled out and treated before Lu-177 PSMA therapy, if possible.)

  • In bone marrow depression

– Total white cell count <2.5×109/L

– Platelet count <75×109/L. However, if the platelet count is stable and the patient does not have a safer treatment option, Lu-177 PSMA therapy can be used. In such cases, it is not clear whether the amount of activity to be injected before the first cycle will be reduced or not.

– A hemoglobin level lower than 8 g / dL is a relative contraindication. In the case of symptomatic anemia, erythrocyte transfusion should be performed before treatment. Lu-177 PSMA therapy may have a positive effect on bone marrow depression due to tumor regression in the bone marrow.

– In the presence of situations that require timely intervention (radiotherapy, surgery) ((eg .; spinal cord compression and unstable fractures) Lu-177 PSMA treatment can be done later, depending on the patient’s condition. Borderline cases should be evaluated within a multidisciplinary tumor council in terms of individual benefit-risk assessment.))

  • Previous myelosuppressive treatments (chemotherapy or bone targeted radionuclide therapy) should be discontinued at least 4-6 weeks prior to PSMA therapy.

 ECOG Performance Scale


Fully active, able to perform all pre-illness activities without restrictions.


There is a limitation in vigorous physical activity, but he can stand and do soft work. For example; mild home and office work


Standing and doing his own work, but unable to work and able to spend more than half of the daylight hours on his feet.


Difficulty self-care, sleeping for more than half of the daylight hours or sitting in a chair.


Cannot self-care, fully dependent on chair or bed.

Preperation Before Lutetium-177 PSMA Therapy

It is important that the patient whose treatment is planned to bring the following information and documents with him during his first application to the Nuclear Medicine Clinic :

  • Latest epicrisis associated with prostate cancer,
  • Pathology results,
  • Blood tests (PSA, complete blood count, sodium, potassium, phosphate, urea, creatinine, alkaline phosphatase, albumin, AST, ALT, LDH, bilirubin, total protein, 24-hour urine creatinine clearance),
  • Whole body bone scintigraphy, CT, MR and Ga-68 PSMA PET/CT reports and original film/CD/DVDs.

How is Lutetium-177 PSMA Treatment Applied?

Treatment Regimens

(For Lu-177 PSMA-167 and Lu-177 PSMA-I&T ligands)

  • Activity administered per treatment: Based on observational data range between 3.7–9.3 GBq (100–250 mCi). Current phase II studies support 6-8.5 GBq (160-230 mCi) standard activities in most cases. An ongoing phase III trial (VISION) applies a standard activity of 7.4 GBq (200 mCi) at 6-week intervals for a total of 4 to 6 cycles..
  • The time interval between treatments is 6-8 weeks.
  • The number of cycles is 2 to 6 (response varies depending on prognosis and kidney risk factors).
  • 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, 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 cumulatively absorbed maximum dose should be spread over the longest clinically possible time.
  • Evaluation of response to treatment: It should be evaluated with PSA and post-treatment scintigraphic imaging at each cycle. In addition, cross-sectional imaging and additional staging studies, preferably PSMA PET/CT, should be performed every two cycles.

Lu-177 PSMA Administration


In principle, no premedication is required in the Lu-177 PSMA treatment. Most patients tolerate treatment well.

Below, there are some general recommendations for the treatment of Lu-177 PSMA, and should be applied taking into account the individual patients’ circumstances :

  • A diuretic may be used after administration to support the clearance of unbound Lu-177 PSMA. In the presence of a dilated non-obstructive renal collecting system, 30 minutes after Lu-177 PSMA injection, 40 mg furosemide injection is recommended. It is important for the patient to sit down after the injection for better kidney drainage.
  • Although its value is controversial, applying cold packs to the salivary glands during the “blood pool phase” may reduce the retention of Lu-177 PSMA in the salivary glands.
  • The most common side effects that can be seen in the first 48 hours after Lu-177 PSMA administration are mild nausea and vomiting. This condition can be easily treated with antiemetic drugs such as Ondansetron. Dimenhydrinate or metoclopramide may help in cases where there is no response. However, prophylactic antiemetic therapy is not mandatory but optional in all patients.
  • In patients with diffuse bone and liver metastases and patients with brain metastases, oral corticosteroids (eg 20 mg / day Prednisolone) should be used for 1-2 weeks starting 1 day before Lu-177 PSMA administration. In other cases, it is optional and depends on the case. Proton pump inhibitors should also be used for prophylactic purposes in patients receiving corticosteroid therapy.

Hydration and Lu-177 PSMA Administration

Before starting treatment, according to the individual cardiovascular and urination conditions of the patients, I.V. or oral hydration should be initiated. 

For treatment, the Lu-177 PSMA is administered by 10-30 sec I.V. bolus injection. In order to reduce the dose of the received radiation, 1.5 mm plexiglass syringe shield is required for beta radiation and lead shield is required for gamma radiation.

In patients with low cardiovascular risk, following administration of Lu-177 PSMA, 500-2000 mL Ringer’s or saline I.V. can be administered by the route at a flow rate of 20 mL/min to reduce the kidney dose. In patients with heart failure, the amount of fluid should be reduced. In cases with urinary incontinence, it is recommended to use a urinary catheter for 24-48 hours to prevent contamination.

Post-Treatment Scanning

After Lu-177 PSMA injection, between 4 and 48 hours at least one whole body scan, preferably SPECT (/CT), should be performed. For this purpose; Medium energy, general purpose, parallel hole collimator and 113 KeV (20% window width) and 208 KeV (15% window width) energy peaks should be used. After Ac-225 PSMA application, post-treatment scanning can be performed using medium energy, general purpose, parallel hole collimator using 78, 218 and 440 KeV energy peaks.

Combination of PSMA Therapy with Other Treatment Options

Combination of Lu-177 PSMA therapy with chemotherapy is not recommended. In addition, there is no data on the combination of both treatments in patients who still have a response to new generation hormone therapies (abiraterone/enzalutamide). However, in patients with brain metastases, Lu-177 PSMA therapy can be combined with external radiotherapy of brain metastases. In addition, individual experience has shown that PSMA therapy in combination with external radiotherapy is possible and safe in patients with painful bone metastases or at risk of fracture.


Follow-up examinations since the initiation of Lu-177 PSMA therapy:

  • Complete blood count; It should be checked every 2-3 weeks (depending on the initial condition), up to 12 weeks after each cycle.
  • PSA as a tumor marker should be followed at 4-week intervals. PCWG3 (Prostate Cancer Clinical Studies Working Group 3) criteria should be taken into consideration in follow-up and interpretation.
  • Basic liver and kidney profile; It should be evaluated every 6-8 weeks.
  • Physical examination; It should be done before each treatment.
  • Post-treatment screening scintigraphy (4-48 hours after application); It both confirms the involvement of Lu-177 PSMA in the lesions and shows the response of PSMA-positive lesions to treatment when performed at later time points.

Follow-up examinations after several cycles of Lu-177 PSMA therapy :

Imaging-based restaging should include a second imaging modality to allow detection of PSMA-negative lesions. For this purpose, CT and MR images, whole body bone scintigraphy or FDG PET/CT imaging can be used as an integrated part of existing PSMA PET/CT or PET/MR examinations. The frequency of restaging 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.


Duration of Lu-177 PSMA treatment is planned according to individual clinical need by carefully evaluating the cumulative absorbed doses by the salivary glands and kidneys. Blood count, general medical condition and inclusion / exclusion criteria should be re-evaluated prior to re-treatment. Repeated Lu-177 PSMA therapy has been administered in up to seven cycles in total in current observational studies without undue toxicity. Repeated treatment every 6-8 weeks allows improvement in hematotoxicity in most cases and this is in line with published protocols.