Ga-68 PSMA PET/CT
Ga-68 PSMA PET/CT;
Indication
Ga-68 PSMA PET/CT is indicated for;
1) In primary staging before surgical procedure and/or radiotherapy planning in high risk disease,
2) To investigate all pathologic tissue with high PSA continues after radical prostatectomy or high PSA recurrence after radical prostatectomy / radiotherapy,
3) Evaluation of response to treatment.
What is Gallium-68 PSMA PET/CT?
Theranostic is an emerging field in the medicine 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 already known, how far it will go and its power to affect the diseased tissue. This approach enables the transition from traditional medicine to personal contemporary 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.
Standard imaging in metastatic prostate cancer traditionally includes MRI, CT and whole body bone scintigraphy. However, the sensitivity of these imaging methods is very low, especially in oligometastatic condition and low PSA levels. On the other hand, there are limitations in specificity for standard imaging modalities. In fact, benign lymph node enlargement on CT or benign bone lesions on bone scintigraphy cause erroneous interpretation. Because of these limitations, new imaging modalities are needed for prostate cancer patients.
Prostate specific membrane antigen (PSMA) is a transmembrane protein expressed on the cell surface of prostate cells, and it is known that the expression of PSMA is also increased with increasing cell dysplasia. Many small molecules have been developed that can bind to PSMA that is a proven good target for prostate cancer. Some of these new molecules have been labeled with radioactive elements, especially Gallium-68, and started to be used in Nuclear Medicine, especially in PET / CT imaging.
Looking at the available scientific evidence, it appears that Ga-68 PSMA PET / CT significantly affects clinical decision making. Of course, it is of great importance to detect small volume metastases early and accurately in prostate cancer by Ga-68 PSMA PET / CT providing superior sensitivity and specificity values compared to alternative techniques.
How Does Gallium-68 PSMA PET/CT Reveal Tumor Focus?
Ga-68 PSMA PET / CT is a non-invasive imaging method that visualizes prostate cancer with the presence of increased prostate-specific membrane antigen (PSMA, glutamate carboxypeptidase II) expression. PSMA is a transmembrane protein found especially in all prostate tissue and PSMA expression is seen in different malignancies, mostly in prostate cancer. Almost all primary and metastatic lesions of prostate adenocarcinomas show increased PSMA expression. Immunohistochemical studies have shown that PSMA expression is increased in the case of de-differentiated, metastatic or hormone-resistant disease and that the expression level is an important prognostic indicator for the disease.
68Ga is a radioactive element with a physical half-life of 67.63 minutes, often obtained from Germanium-68 / Gallium-68 generator systems. Low molecular weight PSMA ligands complexing with 68Ga such as PSMA-11, PSMA-617 and PSMA-I & T were specially prepared for PET / CT imaging and all these radioligands have similar properties in detecting tumor tissue.
Who is Gallium-68 PSMA PET/CT Applied to ?
Existing scientific data support the use of Ga-68 PSMA PET / CT imaging, especially for the detection of prostate originated cancer foci. With this method; Even small metastases can be imaged that could not be detected by conventional imaging methods such as CT, MRI and bone scintigraphy. Ga-68 PSMA PET / CT is mainly used for the following purposes:
European Association of Urology Perspective
Ga-68 PSMA PET / CT imaging in prostate cancer has begun to take its place in major clinical guidelines, such as the “European Association of Urology Prostate Cancer Guidelines”, to detect biochemical recurrence at very low serum PSA levels.
Imaging in patients with biochemical relapse; It has the potential to play a role in the detection of distant metastases and in the detection and localization of local recurrence. In the presence of biochemical recurrence, early detection of metastases is clinically extremely important both after primary radiotherapy and after radical prostatectomy. Since salvage treatments for local recurrence after primary radiotherapy will cause significant morbidity, it is necessary to identify metastatic patients with the highest possible sensitivity in order to avoid the possible morbidity of unhelpful salvage treatments in these patients. On the other hand, standard imaging with bone scan and MRI has a low rate of lesion detection in men with radical prostatectomy with PSA below 2 ng / mL. However, it has been shown that Ga-68 PSMA PET / CT can guide salvage radiotherapy planning by showing residual cancer in this patient group after radical prostatectomy.
Evidence suggests that Ga-68 PSMA PET / CT is much more sensitive than classical bone scintigraphy and abdominopelvic CT in detecting lymph node and bone metastases.
Clinically significant PSA relapse: PSA level, which defines treatment failure, varies depending on the primary treatment (radical prostatectomy or primary radiotherapy). After radical prostatectomy, the PSA cut-off value that predicts metastasis is> 0.4 ng / mL. However, with access to the ultra-sensitive PSA test, PSA increases far below this level can be detected. The definition of failure after primary radiotherapy is an increase in PSA> 2 ng / mL above the rare PSA value, regardless of the (rare) PSA value after treatment.
After the changes added to the Prostate Cancer Guide of the European Association of Urology in 2019, under the heading “imaging instructions in patients with biochemical recurrence” PSMA PET / CT indications are as follows:
| In patients with persistent PSA elevation after radical prostatectomy | to rule out metastatic disease, perform a Ga-68 PSMA PET / CT scan for men with persistent PSA> 0.2 ng/mL |
| After radical prostatectomy, in patients with prostate specific antigen (PSA) recurrence | Perform Ga-68 PSMA PET / CT if the PSA level is> 0.2 ng/mL and imaging results will influence subsequent treatment decisions. |
| In patients with PSA recurrence after radiotherapy | Perform Ga-68 PSMA PET / CT on eligible patients for curative salvage therapy. |
EANM/SNMMI Perspective
Considering the effects of Ga-68 PSMA PET / CT on the staging and management of patients with prostate cancer in different clinical conditions (such as pre-treatment initial staging, restaging after different primary treatments, advanced disease), It is observed that specified disease stage determined by physician before Ga-68 PSMA PET/CT, changes after Ga-68 PSMA PET/CT in 69% of the cases. This change is “upstaging” in 38% of cases and “downstaging” in 30% of cases. This change is valid for all clinical scenarios and, as expected, the lowest effect on staging was found in cases with serum PSA levels ≤0.2 ng / mL after surgery (31%, all “downstaging”).
When we look at the effect of Ga-68 PSMA PET / CT on the treatment approach of prostate cancer patients with different clinical conditions, it was seen that it caused a change in the treatment approach in 57% of the cases. The most common change in the cases was the transition from systemic to focal therapy (16%) and change in focal treatments (10%).
Imaging of Tumor Tissue in Recurrent Prostate Cancer
It is recommended in patients with a PSA value between 0.2 and 10 ng / mL to identify the site of recurrence and possibly directed to salvage therapy. In patients with shorter PSA doubling times (doubling time, PSADT) and higher baseline Gleason scores, higher sensitivity is achieved with Ga-68 PSMA PET / CT. We now understand that conventional imaging (CT, MR, bone scintigraphy) is quite useless at these low PSA levels.
The positivity rates of Ga-68 PSMA PET / CT in different increased PSA levels after radical prostatectomy can be summarized as follows.
| PSA level (ng/mL) | Positive Ga-68 PSMA PET/CT ratio |
| 0 – 0.19 | %33 |
| 0.2 – 0.49 | %42 |
| 0.5 – 0.99 | %59 |
| 1 – 1.99 | %75 |
| >2 | %95 |
| Recurrence Localization | Positive Ga-68 PSMA PET/CT ratio |
| Prostate bed | %27 |
| Lymph node – pelvic | %40 |
| Lymph node – extraprostatic | %21 |
| Bone | %30 |
| Distal organ | %10 |
There is also a tight correlation between PSA doubling times (PSADT) and positive PET / CT PSMA ratios :
| PSADT | Positive Ga-68 PSMA PET/CT ratio |
| Long (>6 ay) | %64 |
| Short (<6ay) | %92 |
Performing Primary Staging Before Surgical Procedure or Radiotherapy Planning in High Risk Disease
In patients with high risk disease (Gleason score> 7, PSA> 20 ng / mL, clinical stage T2c – 3a), the likelihood of lymph node and bone metastasis is increased.
In many studies for primary staging, Ga-68 PSMA PET/CT has been shown to be superior to CT, MRI or bone scanning in detecting metastases. Detection of anatomically undetected lymph node metastases by CT or MRI can also significantly affect patient management. However, the effect of enhanced sensitivity that comes with Ga-68 PSMA PET/CT on overall survival is yet to be answered. In addition, preliminary data showed that Ga-68 PSMA PET/CT gave more accurate results in detecting bone metastases. However, Ga-68 PSMA PET/CT cannot replace pelvic MR in defining the local tumor.
New Clinical Indications
Staging is very important to determine the presence and intensity of tumoral PSMA expression (mainly in metastatic castration-resistant prostate cancer) before and during treatment with PSMA-targeted radioligand (Lu-177 PSMA). Low PSMA expression in target lesions is also a contraindication for radioligand therapy. Another point to be considered is that Ga-68 PSMA PET/CT gives false negative results in approximately 5% of patients with prostate cancer. It has also been reported that metastases (mainly in the liver) may lose PSMA expression in patients with advanced metastatic castration-resistant prostate cancer.
Biopsy Guidance in Patients with a Negative Prior Biopsy but Highly Suspected Prostate Cancer
Preliminary data suggest that Ga-68 PSMA PET/CT may be valuable in guiding repeated biopsies in patients with high suspicion of prostate cancer. In this case, preferably Ga-68 PSMA PET/CT images should be combined with multiparametric MRI.
Evaluation of Systemic Therapy Response in Metastatic Prostate Cancer
The role of RECIST 1.1 in the anatomical assessment of response to treatment is limited by the high prevalence of unmeasurable lymph node and sclerotic bone metastases. Bone scan may cause erroneous evaluation due to flare phenomenon that develops after treatment. Monitoring systemic disease in such an environment could become a potential application area for Ga-68 PSMA PET / CT. However, it has not yet been proven whether Ga-68 PSMA PET / CT overcomes the limitations of other methods and is superior at this time.
PSMA PET/CT Progression (PPP) Criteria
| Progression Criteria | Description |
| ≥2 new PSMA positive lesions | detection of new ≥2 PSMA positive distant lesions |
| 1 new PSMA positive lesion | 3 months after Ga-68 PSMA PET/CT, detection of 1 new PSMA positive lesion plus compatible clinical and/or laboratory data, confirmation by biopsy or correlative imaging within is recommended, but not essential. |
| No new lesions but increase in size | Within 3 months after Ga-68 PSMA PET/CT, detection of an increase in size or PSMA uptake of ≥30 plus consistent clinical and/or laboratory data should be confirmed by biopsy or correlative imaging. |
Special Suggestions for Different Treatments
In cases where response to treatment is evaluated using Ga-68 PSMA PET/CT, it is recommended to wait 4 weeks for chemotherapy and 8 weeks for radiotherapy. It may be necessary to wait even longer after surgery. These recommended time intervals are frequently applied in clinical routine, although there are no prospective data. In fact, the reliable time interval required for Ga-68 PSMA PET/CT imaging is currently unknown.
As seen in animal and human studies, Androgen Deprivation Therapy (ADT) can result in excessive PSMA expression, which can lead to false positive findings. However, ADT can increase the number of true positive findings on the other hand. The effect of ADT and (Androgen Receptor) AR-targeted therapies on Ga-68 PSMA uptake is much more prominent immediately after initiation of treatment. Therefore, evaluation of ADT response with Ga-68 PSMA PET/CT should be performed at the earliest 4-8 weeks after initiation of therapy.
Limited data are available on the use of Ga-68 PSMA PET/CT to evaluate the response to PSMA therapy (e.g. with Lu-177 PSMA-617). However, preliminary data show that the PSMA PET/CT Progression (PPP) criteria can also be applied in this situation.
Turkey Social Security Institution Perspective
Indication of Ga-68 PSMA PET/CT in prostate Ca patients as fallows :
| Staging | It is paid only if it is performed at the third level official healthcare providers* if Gleason score 7 or above and there are suspicious lesions in other imaging methods (Bone Scintigraphy, CT, MR etc.).. |
| Re-Staging | |
| Evaluation of response to treatment |
* Third level official health institution; Training and research hospitals affiliated to the Ministry of Health and private branch training and research hospitals, district polyclinics affiliated to these hospitals, university hospitals and health practice and research centers, institutes and district polyclinics affiliated to these hospitals.
Is Gallium-68 PSMA PET/CT Safe ?
Ga-68 PSMA is not a contrast agent and no side effects (allergic reactions, skin rash, rash, nausea, vomiting, etc.) are expected during application. However, it is necessary to be careful in terms of contrast allergy and other side effects in special cases if intravenous radiologic contrast agents is administering at the same time.
68Ga has a very short half-life such as 68 minutes, and the radiation in the body returns to its natural level at the latest 6 hours after the drug is administered, For this reason, contact with small children and pregnant women should be avoided for the first 6 hours after drug administration.
Radiation exposure due to Ga-68 PSMA PET/CT procedure is approximately 5 mSv. This dose is similar to the dose you would be exposed to with a conventional examination such as X-Ray computed tomography.Preperation Before Gallium-68 PSMA PET/CT
Ga-68 PSMA PET / CT Examination Request
Ga-68 PSMA PET / CT scan request should also include a brief summary of the patient’s diagnosis and oncological history.
The points to be considered in the evaluation of the patient file are as follows:
- Imaging indication
- Prostate cancer specific history:
- Primary Cancer
-PSA and Gleason score
- Biochemical Recurrence
-PSA and PSA kinetics
-Previous Therapies (Eg. prostatectomy, radiotherapy)
- Current prostate cancer drug treatments: Androgen deprivation therapy (ADT, antiandrogen therapy, castration therapy) or other androgen receptor targeted therapy. Recent history of chemotherapy, Radium-223 or PSMA targeted radioligand therapy.
- Disease-related symptoms (bone pain, frequent urination, nocturia, hematuria, dysuria, impotence, erectile dysfunction or painful ejaculation)
- Previous imaging findings
- Disease-related comorbidities
- Non-prostate malignancies
- Allergies
- Renal failure
Patient Preperation
Patients do not need to be fasting for the procedure and can use all their medications. Preclinical data show that PSMA expression is increased in castration-resistant prostate cancer and under ADT. However, more data are needed to evaluate the clinical impact of ADT on Ga-68 PSMA PET/CT performance. Patients should be well hydrated before imaging. Oral intake of 500 mL water 2 hours before imaging will be sufficient. The bladder should be emptied by voiding just before imaging. However, in some cases, high activity remains in the urinary system and may cause “halo artifact” in PET/CT. Activity in the ureters may cause false positive findings. In this case, administration of Furosemide (20 mg, i.v., just before or after i.v. administration of Ga-68 PSMA) may be particularly helpful.
How is Gallium-68 PSMA PET/CT Applied ?
PET/CT imaging was performed approximately 60 minutes after the I.V. bolus injection of Ga-68 PSMA at a dose of 1.8-2.2 MBq/Kg (0.049 – 0.060 mCi/Kg). In cases where there is suspected in the first hour imaging, late imaging until the 3rd hour may be helpful in identifying lesions near the ureter or bladder or in lesions showing low PSMA expression.
Image acquisition and reconstruction protocol example for Ga-68 PSMA PET/CT :
| Patient Preperation | 500 mL water oral intake 2 hours before imaging |
| Activity / Administration | 1.8-2.2 Mbq/Kg, i.v., then rinse with saline |
| Concurrent medication | Furosemid (20 mg, i.v.) |
| Uptake time | 60 min. (acceptable range: 50-100 min) |
| Patient position | Supine, arms above head |
| CT Protocol |
FOV: from base of skull to mid-femur; Phase: portal venous (80 seconds after 1.5 mL/Kg contrast medium) |
| PET/CT Protocol |
FOV: from mid-femur to base of skull, 3-4 min per bed position.
|
Reporting
Defining PSMA Uptake Location, Extent and Intensity
In the general review, priority should be given to the prostate gland/bed, seminal vesicles, regional and distant lymph nodes, bones, lungs, and liver. Particular attention should also be paid to areas that may be associated with symptoms in the request form. In addition to the semi-quantitative values (maximum SUV), Ga-68 PSMA uptake levels of the lesions; to be reported as low, moderate, or intense compared to background involvement. Tumoral lesions generally show higher Ga-68 PSMA uptake than the adjacent background. For each region where Ga-68 PSMA uptake can be detected, the corresponding lesion on CT should also be reported.
Physiologic, Benign and Malign Uptake (other than prostate) and Artefacts
Normal and variable levels of PSMA uptake can be seen in the tissues below:
Physiologic uptake
- Lacrimal Glands
- Salivary Glands
- Liver
- Spleen; including splenosis and acsesory spleen
- small and large intestine
- Kidneys
- Autonomic nervous system ganglia, cervical, most commonly lumbar, stellate, celiac and sacral ganglia
- Radioligand excretion from urinary system, ureter, bladder
Benign Pathologies
- Granulomatous diseases; sarcoidosis, Wegener granulomatosis, tuberculosis, anthracoslicosis
- Benign bone diseases; fibrous dysplasia, healing fracture, Paget’s disease
- Benign neurogenic tumors; schwannoma and other peripheral nerve sheath tumors, meningioma
- Benign soft tissue pathologies; gynecomastia, hemangioma, desmoid tumor, intramuscular myxoma, pseudoangiomatous stromal hyperplasia
Malign Tumors other than Prostate
- Multiple myeloma
- Thyroid Ca; medullary, papillary, follicular
- Breast Ca
- Lung Ca
- Pancreatic NET
- Renal cell carcinoma, metastatic
- Hepatocellulary carcinoma
- Glioblastoma multiforme
Ga-68 PSMA ligands are excreted primarily through the urinary system and collected in the bladder, while a small proportion is cleared through the hepatobiliary system. Therefore, setting the SUV threshold correctly to evaluate Ga-68 PSMA ligand uptake in soft tissue structures adjacent to the bladder is important not to overlook minor local recurrences. Late imaging of the pelvis after administration of normal saline infusion and/or furosemide may be helpful in such situations. Due to the high background activity in the liver, potential liver metastases may not be detected. This is exacerbated by the tendency of liver metastases to lose PSMA expression in advanced metastatic disease. Therefore, in advanced disease, the CT component of PET/CT should be optimized to detect liver metastases.
Immunohistochemical and Ga-68 PSMA PET / CT data have shown that increased PSMA expression due to neovascularization can be detected in non-prostate cancer types such as colon cancer, esophageal cancer, thyroid cancer, lung cancer, kidney cell carcinoma and brain tumors.
Another important uptake is Ga-68 PSMA ligand involvement in the celiac ganglia of the autonomic nervous system, which can cause misinterpretation as retroperitoneal lymph node metastasis.
Ga-68 PSMA PET / CT has not yet been confirmed for evaluation of treatment response in prostate cancer patients. However, in principle, the extent and intensity of PSMA involvement should be reported and compared with previous screenings when it will be used to assess response to treatment.
miPSMA expression scoring ( for Ga-68 PSMA)
| Score | Reporting | Uptake Level |
| 0 | none | < blood pool |
| 1 | low | ≥ blood pool and < liver* |
| 2 | medium | ≥ liver and < parotid gland |
| 3 | high | ≥ parotid gland |
*When using PSMA ligands that are excreted from the liver, such as 18F-PSMA, the spleen is recommended as the reference organ instead of the liver.
miTNM Classification for Ga-68 PSMA PET/CT
| Class | Description |
| Local Tumor (T) | |
| miT0 | No Local Tumor |
| miT2 | Organ-limited tumor, intraprostatic tumor localization is reported on a sextant basis. |
| u | Single focus |
| m | Multiple focuses |
| miT3 | Tumor not limited to the organ, intraprostatic tumor localization is reported on a sextant basis. |
| a | Extension out of the capsule |
| b | Tumor invasion of seminal vesicles |
| miT4 | Tumor invades neighboring structures such as external sphincter, rectum, bladder, levator muscle or pelvic wall other than seminal vesicles. |
| miTr | Local recurrence after radical prostatectomy |
| Bölgesel lenf nodları (N) | |
| miN0 | No positive lymph nodes |
| miN1a | Lymph node metastasis is reported in a single lymph node region on a standard station basis. |
| miN1b | Lymph node metastasis is reported in ≥2 lymph node regions on a standard station basis. |
| Uzak metastaz (M) | |
| miM0 | No distant metastasis |
| miM1 | Distant metastasis |
| a | Extracelvic lymph node metastasis is reported on a standard station basis. |
| b | Bone metastasis, involvement pattern and bones retained in a unifocal or oligometastatic state are reported. |
| c | In other regions; the affected organ is also reported. |
Sextant Segmentation of the Prostate Gland for Ga-68 PSMA PET/CT
| Segmentation | Template for miT2-4 |
| LB | Left basal |
| RB | Right basal |
| LM | Left middle |
| RM | Right middle |
| LA | Left apex |
| RA | Right apex |
Lymph node stations
| Station | |
| miN1a/b | |
| Internal iliac | |
| External iliac | |
| Main iliac | |
| Obturatory | |
| Presacral | |
| Other, pelvic (define) | |
| miM1a | |
| Retroperitoneal | |
| Supradiaphragmatic | |
| Other, extrapelvic |
Bone involvement patterns
| Single Focus |
| Oligometastatic (n ≤ 3) |
| Dissemine |
| Diffuse bone marrow involvement |