Showing posts with label PSMA. Show all posts
Showing posts with label PSMA. Show all posts

Thursday, July 26, 2018

F18-PSMA-1007 - the latest PSMA-based PET indicator

The development of new PET indicators for prostate cancer continues. As we've seen, the Ga-68-PSMA-11 indicator is already making a difference in clinical practice. Many of the new PET indicators have been developed in Germany, although the best one so far before this, F18-DCFPyL was developed at Johns Hopkins.

Researchers in Germany have developed a new PSMA-based PET indicator, F18-PSMA-1007, that seems to be even better. They tested it on 251 biochemically recurrent (after prostatectomy) patients at 3 academic centers.

  • 81% had a recurrence detected
  • 44% had a local (prostate bed) recurrence
  • 41% had a pelvic lymph node recurrence
  • 20% had a retroperitoneal lymph node recurrence
  • 12% in lymph nodes above the diaphagm
  • 40% had bone metastases
  • 4% had visceral organ metastases


Detection rates varied by PSA:

  • 62% in those with PSAs from 0.2-<0.5
  • 75%  in those with PSAs from 0.5-<1.0
  • 90%  in those with PSAs from 1.0-<2.0
  • 94%  in those with PSAs >2.0


Interestingly, those who had ADT in the last 6 months had higher detection rates (92%) compared to those who'd had no ADT recently (78%). This may be because those who had ADT recently had more advanced tumors. There was some early evidence in mice and lab studies (like this one and this one) that ADT upregulated PSMA. One clinical study indicated that ADT improved detection of PSMA. Two studies  (this one and this one) showed no effect of ADT on PSMA detection. More recent evidence indicates use of ADT negatively impacts detection rates. The patient should avoid ADT before getting a PSMA-based PET scan, if possible.

The detection rate among those with PSAs between 0.2-2.0 was 78%, which is comparable to the 88% detection rate reported for men with PSAs between 0.2-3.5 for F18-DCFPyL and much better than the detection rate of 66% reported for Ga-68-PSMA-11 in that PSA range. F18 has an advantage over Ga-68 in having a longer half-life (118 minutes vs 68 minutes) and is more tightly bound to the ligand. Because it is not appreciably excreted through the urinary tract, it can be seen more easily around the prostate - important when the recurrence is near the site of the anastomosis, as most recurrences are. In a mouse study, it was superior to F18-DCFPyL. In a clinical pilot study, they both detected the same tumors.

As of now, the F18 PSMA-based PET indicators seem to be superior, but others are working on ligands that detect other prostate cancer proteins more sensitively and more specifically. Leading candidates are hK2, FMAU, Citrate, Prostate-Stem-Cell-Antigen, , DHT/androgen receptor, uPAR receptor, VPAC receptor, or multiple ligands.

Also see:




Monday, October 16, 2017

Does Lu-177-PSMA-617 increase survival?

We have enthusiastically reported the encouraging outcomes of the early clinical trials of the radiopharmaceutical Lu-177-PSMA, most recently at this link. Based on reduction in PSA, it performs well. But medicines have no real benefit if all they do is treat PSA. We want medicines that increase survival.

Rahbar et al. reported the outcomes of 104 patients treated with Lu-177-PSMA-617 at University Hospital Muenster, Germany. All patients had metastatic castration-resistant prostate cancer (mCRPC) and had already received docetaxel and at least one of abiraterone or enzalutamide. After the first of an average of 3.5 cycles, they had the following outcomes:
  • 67% of patients had some PSA decline
  • 33% of patients had a PSA decline of at least 50%
  • Median overall survival was 56 weeks (13 months)
The authors conclude:
177Lu-PSMA-617 RLT is a new effective therapeutic and seems to prolong survival in patients with advanced mCRPC pretreated with chemotherapy, abiraterone and/or enzalutamide. 
But is this conclusion justified? It's hard to know without a prospective clinical trial where patients are randomized to receive the radiopharmaceutical or standard-of-care. The best we can do is look at the overall survival from clinical trials involving patients with symptomatic mCRPC. In the "ALSYMPCA" trial of Xofigo, among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), overall survival was:
  • 14 months with Xofigo
  • 11 months with placebo
The ALSYMPCA trial was conducted before abiraterone and enzalutamide were approved, so it is impossible to know how prior treatment with one of those might have changed survival. There have been a couple of small trials of "third-line" medicines after docetaxel and abiraterone were used.

In a non-randomized trial among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:
  • 9 months with cabazitaxel
In a Danish study among 24 mCRPC patients after treatment with docetaxel and abiraterone, overall survival was:
  • 5 months with enzalutamide
So these data suggest that Lu-177-PSMA-617 may have prolonged life more than third-line treatment with another taxane or another hormonal agent. However, we expect much cross-resistance between abiraterone and enzalutamide, and resistance building up with prolonged use of taxanes. It is always hazardous to compare patient outcomes or declare success when they have not been randomized. Certainly there is enough suggestive data to warrant a Phase 3 randomized clinical trial.



Tuesday, September 5, 2017

A new Lu-177-PSMA ligand has good results in a new study

Targeted nuclear medicine has shown some impressive outcomes in several small studies, mostly conducted in Germany. Most of the studies have used a radioactive beta-particle emitter, Lutetium 177, attached to a ligand that has high and specific affinity for prostate cancer cells. Most medicines developed for this purpose have a ligand that attaches to Prostate-Specific Membrane Antigen (PSMA), a protein found on 90% of all prostate cancer cells. The ligand for Lu-177-PSMA has to have a "grappling hook" on one end (called a chelator) that holds onto the Lu-177. On the other end is a "magnet" of sorts that binds tightly to the PSMA. The beta particles then kill the cell that the ligand attaches to and some nearby cells as well.

There are also ligands that attach to prostate cancer proteins other than PSMA, and radioactive elements other than Lu-177 that are in clinical trials. This is a rapidly developing field.

The new ligand is called PSMA-I&T (imaging and therapy) or sometimes PSMA-DOTAGA. The ligand used in most of the other studies was PSMA-617 (also known as PSMA-DKFZ) or PSMA-J591. The ideal ligand attaches strongly to PSMA in prostate cancer tumors and to nothing else. Importantly, it should not accumulate in the kidneys to a great extent because it could damage them.

Last year, the Central Clinic of Bad Berka, Germany reported on 56 patients treated with Lu-177-PSMA-I&T (see this link). 80% of treated patients had a PSA response and toxicity was minor. Heck et al.  at the Technical University of Munich reported on 19 metastatic castration-resistant patients who were treated with 7.4 GBq per cycle and up to 4 cycles.
  • In 56%, PSA decreased by at least 30%
  • In 33%, PSA decreased by at least 50%
  • In 11%, PSA decreased by at least 90%
  • Complete remission of metastases in 5%
  • Metastases stayed stable in 63%
  • Metastases progressed in 32%
  • Performance status was stable or improved in 74%
  • In those with bone pain, it was reduced partially or completely in 58%
  • Mild (Grade 1 or 2) toxicities included dry mouth (37%), anemia (32%), and platelet loss (25%)
  • There were no severe (Grade 3 or 4) toxicities.
  • There was no kidney toxicity up to 40 GBq (see this link)
(Update 11/2018) Heck et al. updated the above with information on 100 patients. They were heavily pre-treated with a median of 3 pre-treatments. In fact, they were required to have had Zytiga or Xtandi, and at least one cycle of taxane chemo. They were all mCRPC and 35% had visceral metastases. They may have had up to 6 cycles of Lu-177-PSMA-617 (average was 3.2 cycles).
  • In 38%, PSA decreased by at least 50%
  • Median clinical progression-free survival was 4.1 months
  • Median overall survival was 12.9 months
  • Treatment-emergent hematologic grade 3/4 toxicities were anemia (9%), thrombocytopenia (4%), and neutropenia (6%)
A meta-analysis looked at the PSMA-I&T and PSMA-617 ligands in relation to the PSMA-J591 ligand. With a combined sample size of 369 patients across 10 studies, Calopedos et al. reported that:

  • 68% of patients had some PSA decline
  • 37% of patients had a PSA decline of at least 50%
  • More patients had a PSA decline with the PSMA-I&T and PSMA-617 ligands, but there was a wide range of outcomes

These early indicators look good. Even if it just stabilizes performance status and mitigates bone pain in these end-stage patients, there is an important benefit. Of course, what we really want to see is evidence that it increases overall survival

While PSMA-I&T was developed to be a good ligand for imaging purposes as well as therapeutic purposes, a recent study found that, when used with Ga-68 (a positron emitter), PSMA-HBED-CC (also known as PSMA-11) was slightly better at detecting metastases (see this link). Another PSMA ligand, DCFPyL, that incorporates the positron emitter F18 into the ligand more tightly (avoiding chelation, which can easily be reversed), seems to be superior to the Ga-68-PSMA-HBED-CC PET tracer (see this link). Both DCFPyL PET and Ga-68-HBED-CC PET are in numerous clinical trials in the US and Canada. Lu-177 is a gamma emitter that can be seen by a gamma camera or via SPECT. However, it is usually used in conjunction with a positron-emitter in order to obtain a superior image.

Readers may wish to read these other articles on this subject:

Will Lutetium-177-anti-PSMA be the next Xofigo?
Lu-177-PSMA update
Lu-177-PSMA: another update
First in-human trial of Actinium-225-PSMA-617
Ac-225-PSMA-617 extends survival (update)
Ac-225-PSMA-617 (update)
I-131-MIP-135, a new radiopharmaceutical, in clinical trial at Memorial Sloan Kettering




Friday, January 27, 2017

I-131-MIP-1095, a new radiopharmaceutical, in clinical trials at Memorial Sloan Kettering

There are few radiopharmaceuticals in clinical trials in the US (there are several in use in Germany), so when a new one is announced, we take notice. I-131-MIP-1095 has had a very limited clinical trial in Germany in 28 patients, and will now be tried in the US.

Like Lutetium 177, Iodine 131 is a beta particle emitter (see this link). It's beta particle energy is somewhat higher, so that it can penetrate greater distances through tissue - up to 3.6 mm, compared to 1.9 mm for Lu-177. This is an advantage in that it can destroy larger tumors, but it is a disadvantage in that it may destroy more healthy tissue, causing hematological and renal side effects. It is also similar to Lu-177 in that its uptake in human tissues can be detected using a gamma ray camera or SPECT detector. Because gamma ray detection does not afford the image quality that PET/CT does, it may be combined with a positron emitter, I-124. Lu-177 is sometimes combined with Ga-68 for the same purpose. This combination of therapeutic and diagnostic (sometimes called theranostic) may be useful in tailoring the dose to the patient based on individual uptake characteristics.

The molecule (or ligand) that the I-131 is attached to is MIP-1095. MIP-1095 is attracted to the PSMA protein on the surface of 95% of prostate cancer cells. Although it is highly specific for prostate cancer, there are other tissues that express PSMA, especially the salivary glands and lacrimal glands. It is excreted by the liver and kidneys, and may show up in the intestines, and the lower urinary tract. The dose to the kidneys may limit the amount of the pharmaceutical that may be given to the patient.

A group from the University Hospital Heidelberg, Zechman et al., treated 28 metastatic castration-resistant patients with I-131-MIP-1095 with the following results:

  • In 61%, PSA was reduced by >50%. This is better than the response seen with Lu-177-PSMA-617 in these trials and in this one.
  • PSA decreased in 21 of 25 patients, increased in 4.
  • 85% had complete or moderate reduction of bone pain. 
  • 25% had a transient slight to moderate dry mouth, which resolved in 3-4 weeks.
  • White blood cell count, red blood cell count and platelets declined during treatment, but there were only 3 cases of grade 3 hematologic toxicity, often in patients with low blood counts at baseline.
  • No renal toxicity was observed.
  • The effective dose to cancer cells was higher than for Lu-177-PSMA-617, red marrow and kidney doses were similar, and liver dose was lower.

The clinical trial that is now recruiting at Memorial Sloan Kettering, is a Phase 1 trial to find the best dose of I-131-MIP-1095 among patients with metastatic castration-resistant prostate cancer. Doses will be administered 12 weeks apart for up to 5 cycles or until dose-limiting toxicity is observed (monthly assessments). Interested patients in the New York City metropolitan area should call the contacts listed on the bottom of this trial description.

Sunday, December 11, 2016

PET scans for prostate cancer

In the last few years there has been an explosion in the number of new PET scan indicators. I thought it a good idea to provide some background and an update.

Bone scans

PET scans may be understood as an improvement over bone scans. The traditional way of finding distant metastases is to use a technetium bone scan and CT. There are several problems with bone scans:
  • they show bone overgrowth, which may be bone metastases, but may just be arthritis or old injuries
  • only a bone biopsy can tell for sure, and it's not often feasible when the suspected mets are small or inaccessible
  • they reveal few mets when PSA is below 10-20 ng/ml or when PSA is stable
  • they only show bone mets, not soft tissue
The main advantage is that they are relatively inexpensive.

The principal uses are: 
  • to rule out bone mets in high risk patients prior to curative treatment
  • to diagnose metastases that may respond to chemo, Xofigo, or spot radiation
  • to track response to treatment among metastatic patients.

PET SCAN USES

Inherent limitations

The new PET scans are better than previous ones in terms of the size of the metastases they can detect, but they do not detect all metastases.
  • A cancer cell is many times smaller than the resolution of the CT or MRI. 
  • The activity of the cancer cell seems to influence whether it is detectable on any of the scans. 
  • There is "noise" in even the most specific tracer, with no sharp delineation between signal and background.
Salvage Radiation

The most important use of these new PET scans is to rule out salvage treatment when it would be futile. For men who have persistently elevated PSA after prostatectomy, or who have had a recurrence (nadir+2) after primary radiation treatment, a PET scan showing distant metastases can spare the man the ordeal and side effects of salvage treatment.

The FDA has approved Ga-68-PSMA-11 PET/CT for detection of recurrences after prostatectomy or radiation. They have also approved Axumin PET scans and C-11 Choline PET scans (at Mayo) for this purpose.

For salvage after primary radiation failure, it is necessary to locate areas within the prostate where the cancer may still be localized.  Memorial Sloan Kettering and the Mayo Clinic have effectively used PET scans to target areas within the prostate for salvage focal ablation or brachytherapy.

For salvage radiation after prostatectomy, it may be possible to identify areas of the prostate bed where spread is evident. While the entire prostate bed must be treated (most of the prostate cancer is below the limit of detection of even the most accurate PET/MRI scan), some radiation oncologists like to provide an extra boost of radiation to the detected cancer foci.

For salvage radiation after primary radiation therapy, whether focal or whole gland (see this link), a PSMA PET scan combined with an mpMRI may be able to detect areas within the prostate that still have cancer. PSMA PET scans may cause false positives if used alone to detect cancer in and around the prostate, because they are excreted in the urine. Some of the newer PSMA PET scans (e.g., F18-PSMA-1007 and F18-rh-PSMA-7) have less renal clearance.

There has been accumulating evidence in the last few years (see this link) that very early salvage radiation treatment may improve salvage radiation outcomes over waiting until the PSA has risen above 0.2 ng/ml. Unfortunately, none of our PET indicators are any good at detecting metastases when PSA is below 0.2 ng/ml. It is unlikely that there are any distant metastases when PSA is that low, but there are some relatively rare forms of prostate cancer that metastasize without putting out much PSA. This leaves the patient without any assurance that salvage radiation will be successful. Perhaps the new PORTOS genetic test will be able to detect distant metastases biochemically, but this remains to be proven.

Pelvic Lymph Node (LN) Treatment

For men diagnosed with high risk prostate cancer, a difficult question is whether the pelvic lymph nodes ought to be treated, either with radiation or with pelvic lymph node dissection. Nomograms based on disease characteristics are used to determine whether the pelvic LNs merit treatment, but such nomograms are often inaccurate. A CT scan can sometimes identify lymph nodes enlarged (>1.2 cm) due to cancer. However, some LNs are only slightly enlarged (0.8-1.2 cm), and some cancerous LNs are not enlarged at all (<0.8 cm). LNs are usually enlarged by infection, so size alone is not a good indicator of cancer. An advanced PET scan can sometimes detect cancerous LNs. This may aid the decision on whether to have whole pelvic treatment for men with high risk cancer. Men who have already had radical prostate therapy that may have included radiation (primary or salvage) to other areas (i.e., the prostate or prostate bed) may face a similar decision as to whether to treat the pelvic LNs with radiation.

Just as it is necessary to irradiate the entire prostate bed and not just the detected foci when giving salvage radiation after prostatectomy, it is probably necessary to treat the entire pelvic LN area, and not just individual LNs, when cancer is detected anywhere in the pelvic LN area. Of course, such a decision must be balanced against the risk of side effects. There are ongoing clinical trials (RTOG 0534 for salvage therapy and RTOG 0924 for primary therapy) to determine whether such treatment provides any survival advantage when LN involvement is suspected. The STAMPEDE trial included an arm where patients were node positive (but negative for distant metastases) and were treated with radiation. Short term follow-up demonstrated an improvement in failure-free survival of 52% among those who had treatment.

Ruling out distant spread where it seems to be localized

PSMA PET scans have been approved to detect prostate cancer in high-risk patients. PSMA PET scans provide a critical decision-making tool because it may be able to answer the following questions for the first time:
  1. Is the cancer still confined to the prostate capsule?
  2. Has the cancer spread to the prostate bed or to surrounding organs?
  3. Has the cancer spread to pelvic lymph nodes?
  4. Has the cancer spread to non-local lymph nodes, bone, or visceral organs?
Giving extra radiation to known tumors

While modern dose-escalated doses of radiation of very good at eradicating tumors, results can be improved even further if focused boost doses are given to areas in the prostate, the prostate bed, and pelvic lymph nodes that are proven to be cancerous with a PET scan. The excellent results are described here.

Oligometastatic radiation of distant metastases

Although some have theorized that there is a stage in prostate cancer metastatic progression where the cancer is still curable, or where it can be delayed by removal of 1-3 detectable metastases, this theory has never been proven. In fact, a meta-analysis this year (see this link) showed that metastatic progression continues in almost all men despite such treatment. The possibility remains that progression may be slowed by spot treatment, although this remains uncertain as well. The natural history of metastatic progression is often very slow in early stages, with years between the first few metastases. The reason for this may be because the tissue in metastatic sites must first be biochemically transformed by signals from micrometastases in order to accommodate the growth of larger metastases. This preparation of fertile "soil" in which metastatic "seeds" can grow may take some time. PET scans for detection undoubtedly introduce lead-time bias into the calculation; i.e., the time between the first and second detected metastasis is certainly longer because a more sensitive PET scan was used, and not necessarily because the first detected metastasis was spot-treated.

In spite of the uncertainty concerning efficacy of spot treatment, patients often want to treat whatever can be detected. When such metastases are detected with sensitive PET scans and are in locations amenable to spot treatment with SBRT, and there is minimal risk of radiation damage to nearby organs, it is hard to argue against such use. However, the patient should understand that there is so far no evidence that such treatment will provide any benefit. He should also understand that detectable metastases in distant sites means that his cancer is systemic. There are thousands of circulating cancer cells and undetectable cancer cells already lodged in tissues. For this reason, it is never a good idea to delay systemic therapy (e.g., hormone therapy) in order to wait for PSA to increase to a point where metastases become detectable on a PET scan. 

Palliative treatment of metastases

Metastases can cause pain and interference with organ function. Bone scans can find larger bone metastases, and they are the ones most apt to cause pain, fracture, or spinal compression. Metastases in weight-bearing bones may be spot-radiated with SBRT to prevent such problems and to relieve pain. In the unusual event that a bone scan can't locate them accurately enough for SBRT treatment, a PET scan may be used.

Bone scans do not detect metastases in soft tissue, while most PET scans (other than the NAF18 PET) can. A PET scan may locate metastases in organs that may be biopsied or treated with radiation or other therapies, like embolization or ablation.

Multiple metastases

The CHAARTED study has taught us that prostate cancer with multiple distant metastases behaves in a different way and reacts to different therapies compared to prostate cancer with a low metastatic burden. Although the metastatic burden in the CHAARTED study was based on bone scan and CT, there may be a potential to identify patients who may respond to earlier systemic therapy if a PET scan were to be used. This use has yet to be explored.

Tracking success of treatments (radiographic progression)

PSA is not always the best measure of whether a treatment is successful and ought to be continued. Because they destroy cancer cells, some therapies may actually raise the PSA level for some time immediately following treatment. Chemotherapy does not always immediately reduce PSA, but the patient wants to know whether the potentially toxic treatment should be continued. Most of the time, serial bone scans can provide an adequate radiographic assessment. However, in patients with low PSA or low metastatic burden, serial PET scans may sometimes provide a more accurate assessment.

Initial detection, active surveillance, focal therapy, dose painting

Just as multiparametric MRIs can be used to detect significant prostate cancer when suspicion remains after a first negative biopsy, a PET scan can conceivably be used for such a purpose (as in this clinical trial). PET scans can also be used to track progression of prostatic foci in patients on active surveillance. It is hard to justify the cost for such purposes, and there is as yet no evidence that it is any better than a multiparametric MRI. In light of the recent evidence that multiparametric MRI may fail to delineate up to 80% of detected prostatic index tumors, they may find future use of PET/MRI in contouring treatment areas for focal ablation and for dose painting (see this link).

The FDA has approved Ga-68-PSMA-11 PET/CT at UCLA and UCSF for unfavorable risk prostate cancer.


How PET scans work

Positron Emission Tomography (PET) is a way of creating a 3D anatomical image. Instead of using X-rays, as a Computerized Tomography (CT) scan does, it detects positrons, which are positively charged electrons (which do not exist in nature). When a positron encounters a normal negatively-charged electron, they annihilate each other and release 2 gamma rays in opposite directions. When the machine detects such a pair of gamma rays, it extrapolates their source position, putting an image together. The PET scanner is combined with a CT scanner in the same device in order to provide anatomic detail.

As a cautionary note, PET scans do expose the patient to significant amounts of ionizing radiation from both the PET indicators and the simultaneous CT scan. It is not something one wants to do frequently.

PET emitters are short-lived radioisotopes that are created in a nearby cyclotron. Commonly used ones include carbon 11 (C11), fluorine 18 (F18), gallium 68 (Ga68), copper 64 (Cu64), zirconium 89 (Zr 89), and iodine 124 (I124). The choice of which one to use is based on cost, access, half-life, strength of signal, and ease of integration with the ligand. C11, for example, has an extremely short half life of only 21 minutes. This means it has to be manufactured very nearby where it will be incorporated into a ligand (like acetate or choline), and must be used immediately. F18 has a longer half-life (118 minutes) and has excellent detectability, but interferes somewhat with metabolism of acetate or choline. I124 has a long half-life (4.2 days) which may be too long for a patient who may have to remain isolated for the duration.

PET emitters are often chemically attached (chelated) to molecules, called ligands, that have particular affinity for prostate cancer cells. Some ligands are metabolically active, meaning they are food for the cancer cell, but not as much for healthy cells. Other ligands are created to attach to specific binding sites on the surface or inside prostate cancer cells. 

NaF(18) PET for bone metastases

Sodium fluoride (NaF18) replaces hydroxide with positronic fluoride when hydroxyapatite, the mineral that constitutes our bones, is actively accumulating in bone metastases. It is our most sensitive tool for detecting bone metastases. Fourquet et al. found that in the same patients, NaF18 detected 91% of bone metastases while DCFPyL detected only 46%.

Metabolic ligands

Because rapidly growing cancer cells metabolize a lot of glucose, fluoro-deoxy-glucose (FDG) has long been used in PET scans for cancer. Prostate cancer in its early stages does not metabolize glucose readily, so FDG can't be used until later stages.

Prostate cancer cells do metabolize fats, consuming choline and acetate. C-11 choline and acetate overcomes the interference problem of F-18 choline and acetate, but is very difficult to work with. Although the FDA has approved the C-11 Choline PET, only the Mayo Clinic offers it in the US. A few sites offer the C-11 Acetate PET, but it is expensive. It also requires a fairly high PSA, ideally ≥ 2.0 ng/ml, or fairly large metastases, to detect anything.

Fluciclovine has recently been FDA approved. It is incorporated into prostate cancer cells as part of amino acid metabolism. It can detect somewhat smaller metastases at lower PSAs.

PSMA ligands

95% of prostate cancers express a protein called Prostate-Specific Membrane Antigen (PSMA) on the surface of cells. There are a variety of ligands that are attracted to it. Some of the ligands are antibodies (like J591), some are shortened antibodies (called minibodies, like Df-IAb2M), and some are small molecules (peptides, like PSMA-HBED-CC or DCFPyL). PSMA-targeted ligands may accumulate in salivary glands, tear glands and kidneys, and urinary excretion may interfere with readings in the prostate area. PSMA has also been found on the cell surface of some other kinds of cancer. New PSMA ligands are still being developed and tried. So far, the one that seems to have the highest specific affinity for PSMA are the F18-based ligands (F18-DCFPyL, F18-PSMA-1007, and F18-rh-PSMA-7). They detect more metastases at lower PSA than the others. 

As prostate cancer progresses, PSMA expression reduces and the cancer metabolizes glucose to a greater extent. Then, it will be detected by FDG PET scans.


Other ligands

There are other prostate cancer-specific molecules for which ligands have been developed and to which positron emitters have been attached.  One of the most promising is the bombesin or RM2 ligand that attaches to the gastrin-releasing peptide receptor (GRPR) on the prostate cancer cell. In pre-clinical studies, it outperformed C-11 Choline. Clinical trials have started. Clinical trials have begun on several PET ligands that are designed for other receptor sites: human kallikrein-related peptidase 2 (hK2), FMAU, Ga-68-Citrate, I-124-Prostate-Stem-Cell-Antigen, Ga-68-DOTATATE (Somatostatin receptor), F18-DHT (androgen receptor), Cu-64-DOTA-AE105 (uPAR receptor), Cu-64-TP3805 (VPAC receptor). or multiple radiotracers.

The winner (so far) is...

Based on clinical trials, below are various PET indicators in approximate rank order of their sensitivity to detect recurrent prostate cancer, and their specificity for detecting it exclusively:
  1. F18-PSMA-1007
  2. F18-rhPSMA-7
  3. F18-DCFPyL
  4. F18-DCFBC
  5. Ga68-PSMA-HBED-CC (Ga68-PSMA-11)
  6. Fluciclovine (F18 - FACBC)/ Axumin
  7. C11-Choline/ C-11-Acetate
  8. F18-Choline
  • NaF18 (note: best for detecting bone metastases)
  • F18-FDG (note: better in late-stage PCa)
The following table shows the percent of patients who had metastases detected at various PSAs. F18-PSMA-1007 and F18-rhPSMA-7, are experimental PET indicators that are cleared quickly from the bladder, and are the best so far. F18-DCFPyL is much better than Ga68-PSMA at low PSA.  At PSAs between 0.5-3.5 ng/ml. it detected prostate cancer in 88% of recurrent patients, while Ga68-PSMA-11 only detected prostate cancer in 66% of the same patients - an improvement in sensitivity by a third. Next in line is fluciclovine, which was recently FDA approved. In 10 patients screened for recurrence at a median PSA of 1.0 with both Ga68-PSMA-11 and fluciclovine, the PSMA scan detected cancer in 5 of the 10 men that were negative on fluciclovine. In addition, positive lymph nodes were detected in 3 of the men using the PSMA scan that were undetected with fluciclovine (see this link). Most other PET indicators, like C-11 Choline or Acetate, or NaF18 are not at all reliable when PSA is less than 2.0.


Percent of patients in whom prostate cancer was detected by the PET indicator, broken down by the PSA of the patients


PSA range

Source

PET Indicator

<0.2 ng/ml

0.2- 0.5 ng/ml

0.5 -2.0 ng/ml

> 2.0 ng/ml


F18-DCFPyL



88% (0.5-3.5)



(1)

Ga68-PSMA-HBED-CC



66%  (0.5-3.5)


F18-rh-PSMA-7 (experimental)


71%

86% (0.5-1.0)

86% (1.0-2.0)

95%

(11)

F18-PSMA-1007 (experimental)


86%

89% (0.5-1.0)

100% (1.0-2.0)

100%

(12) (13)

F18-DCFPyL


48%

50% (0.5-1.0)

89% (1.0-2.0)

94%

(9)

F18-DCFPyL


38%

63% (0.5-1.0)

83% (≥ 1.0)


(14)

Ga68-PSMA-HBED-CC

31%

54%

88%

(2)

Ga68-PSMA-HBED-CC


58%

73% (0.5-1.0)

93% (1.0-2.0)

97%

(3)

Ga68-PSMA-HBED-CC


50%

69%

86%

(4)

F18-FluoromethylCholine


12.5%

31%

57%

Ga68-PSMA-HBED-CC



36% (PSA<1, PSADT>6 months)

95% 

(PSADT<6 months)

(5)

Ga68-PSMA-HBED-CC

11.3%

26.6%

53.3% (0.5-1.0)

71.4% (1.0-2.0)

95.5%

(6)

Ga68-PSMA-HBED-CC

33.3%

41.2%

69.2% (0.5-1.0)

86.7% (1.0-2.0)

94.4%(2.0-5.0)

100% (>5.0)

(7)

Ga68-PSMA-HBED-CC

43%

58%

72% (0.5-1.0)

84% (1.0-2.0)

90% (2.0-5.0)

(13)

Fluciclovine


37.5% (0.2-1.0)    77.8% (1.0-2.0)

88.6%

(8)

C-11 Choline


28%

46% (0.5-1.0)

62% (1.0-2.0)

81%

(10)


PET/MRI

PET scans are usually combined with simultaneous CT scans for image resolution. Siemens has a device that simultaneously provides a PET scan and an MRI. This enables  greater image resolution and the detection of smaller metastases than is possible with a PET/CT. (GE and Philips manufacture dual scanners rather than an integrated single scanner). The PET/MRI exposes the patient to a much lower dose of ionizing radiation than the PET/CT. These devices are expensive, and are only available at a few large tertiary care facilities. In one PET/CT vs. PET/MRI comparison using Ga-68-PSMA, the PET/MRI was able to detect 42% more metastases in recurrent patients, 10% more lymph node metastases, and 21% more bone metastases. In the US, PET/MRIs are in use at Mass General, Johns Hopkins, Stanford, UCSF, Washington University, Cleveland Clinic, and Memorial Sloan Kettering and several others.

Cost/Availability

So far, only Ga-68-PSMA-11, FDG, C11-Choline, and Fluciclovine are FDA approved for prostate cancer detection. NaF is approved for clinical trials and registries only. FDA approval opens the way for Medicare and private insurance to approve and pay for them. Sometimes, insurance plans will agree to pick up the cost. Otherwise, patients who want them must pay out of pocket, if they are available. Ga68-PSMA-11, while FDA-approved at UCLA and UCSF so far, costs $3,000  out of pocket. Hopefully, Medicare/insurance will reimburse soon.

Clinical trials

All of the newer PET tracers require validation with larger sample sizes. While there are some diagnostic tests that have a "gold standard" against which performance can be evaluated, this is problematic for detecting metastases. A positive finding can often be confirmed with a biopsy, so a PET scan's positive predictive value (true positives and false positives) can be ascertained. But there is no easy way to determine whether negatives were true or false in live patients.

F18-DCFPyL is available for free in a trial at NIH for free among any men who are (1) high risk or (2) recurrent (see this link). It is available as a PET/MRI for specific purposes at the  Northwestern University.

It is also available at Johns Hopkins, where it was first developed, for a wide range of indications if ordered by any of their physicians Contact details are available here, There are several studies in Canada: in BC.

Ga68-PSMA-11 is approved at UCLA and UCSF and is available in a clinical trial in the US, including one with a PET/MRI, at  Cleveland Clinic

Fluciclovine is available almost everywhere in the US, and is covered by Medicare for recurrent patients.

If you are interested in one of those PET scans for an indication outside of the clinical trial, call the contact anyway. Some are planning clinical trials for expanded indications shortly, and some may make the PET scan available for purchase outside of the clinical trial. Inquire about cost and get pre-authorization from your insurance company if you can. These can be very expensive.