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  1. Jim Marshall (not a doctor) said ... PSMA (Prostate Specific Membrane Antigen) is a molecule found naturally in the body. PSMA is often found in great numbers on the surface of prostate cancer cells. Doctors are currently running trials attaching radioactive molecules to the PSMA molecule. Some radioactive molecules are picked because they light up on a PET scan. Such scans are often called PSMA scans. The best known in Australia is the Gallium-68 PET/CT scan. Some radioactive molecules are picked because they cause damage to nearby cells. The best known in Australia is Lutetium-177. Some of our members have taken part in trials of Lutetium-177 in Australia. Some got a useful response, some did not. The reason for the mildly sensational title of the article below is that there seems to be a best time to attack prostate cancer with Lutetium-177. Researchers are now trying to find that sweet spot. An important point in the article for any man considering Lutetium-177 treatment: Having a F18 FDG (Glucose) PET scan before proceeding could save you from likely unsuccessful treatment. Clinical trials will likely be doing this as a matter of course. ... end Jim If you are the kind of person who is keen to know many of the technical details of your disease, our fellow organization, USA based THE "NEW" PROSTATE CANCER INFOLINK, often goes deeper into such matters than we do. The following article, by well-know prostate cancer patient advocate Allen Edel, is published with their permission. Why lutetium-177-PSMA treatment sometimes may not help, and may even harm Posted on December 19, 2019 by Sitemaster 2 Votes Lu-177-PSMA usually improves survival We’ve seen in a couple of small trials in Germany and Australia that Lu-177-PSMA seemed to provide better than expected survival. In Germany, average (median) overall survival was 12.9 months across 104 patients. In Australia, average (median) overall survival was 13.3 months across 50 treated patients. In both trials, all or almost all patients had already received taxane chemotherapy and either enzalutamide (Xtandi) or abiraterone acetatet (Zytiga). There was no control group in either trial, so we can only guess at what overall survival would have been without the therapy. In the ALSYMPCA trial of radium-223 (Xofigo), among the subgroup of patients who had received docetaxel for their painful mCRPC (see this link), median overall survival was 14.4 months with Xofigo vs. 11.3 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. In a recent trial of cabazitaxel (Jevtana) as a third-line therapy, after docetaxel and either abiraterone or enzalutamide, median overall survival was 13.6 months for Jevtana vs. 11.6 months for the other second-line hormonal agents. So in heavily pre-treated patients, Lu-177-PSMA seems to improve survival about as well as Xofigo or Jevtana when used as a third-line therapy. We will get a better handle on the actual survival benefit when we get the results of the VISION trial next year. PSA is not always a good indicator of effectiveness, as has been found for Xofigo and sipuleucerl-T (Provenge). Lu-177-PSMA reduced PSA in about two-thirds of treated patients in most studies. That leaves about one-third of patients who derived no benefit (even though they had PSMA-avid tumors), and waterfall plots showed that a few patients had large increases in PSA following PSMA-targeted therapy. It is worth noting that the PSMA protein contributes to the survival of the cancer, and just the PSMA ligand that attaches to it has some activity in delaying progression, even without a radioactive component (similar to the way an anti-androgen attaches to the androgen receptor, delaying progression). It is also worth noting that ADT initially increases PSMA expression, but decreases its expression with continued use. The opportunities are: To select patients who are likely to benefit To give alternative therapies (like Jevtana) to patients who are unlikely to benefit To provide adjuvant therapies that may increase survival PSMA avidity — optimal point in time It has long been known that PSMA is a moving target. The advent of PSMA PET scans has enabled us to track PSMA expression. Cancers that express a lot of PSMA (called PSMA-avid tumors) can be distinguished from cancers that express very little. Radiologists determine avidity by comparing the uptake of the tracer in cells that express PSMA to the uptake of the tracer in cells known to not express PSMA. Early low-grade prostate cancer does not express PSMA at all. Higher grade prostate cancer may express some PSMA. PSMA expression really starts to take off when the cancer metastasizes, although it is highly variable between patients. About 90 to 95 percent of metastatic men express at least some PSMA on their prostate cancer cells. At some point, however, as genomic breakdown continues, PSMA is no longer expressed by metastases. Thus, there is an optimal point for treating each patient with PSMA-targeted therapy. Treatment too early — or too late — may exert selective pressure on the predominant non-PSMA-types, allowing them to take over. Michael Hofman and others at the Peter MacCallum Cancer Center in Melbourne (see this presentation and this link) have initiated several clinical trials using Lu-177-PSMA at earlier stages of disease progression: #lutectomy trial (Declan Murphy, PI) is treating PSMA-avid high-risk patients with Lu-177-PSMA, followed by prostatectomy and pelvic lymph node dissection #upfrontPSMA (Arun Asad, PI) is treating patients first diagnosed with high volume metastases with Lu-177-PSMA + ADT + docetaxel vs ADT + docetaxel. Other opportunities for early use include Lu-177-PSMA treatment for those in the following settings: Active surveillance Persistent PSA after prostatectomy Salvage treatment after first recurrence Salvage treatment after second recurrence Metastatic CRPC before docetaxel or advanced hormonal therapies Non-metastastic (on bone scan/CT) CRPC before docetaxel or advanced hormonal therapies Centers in Germany may be willing to treat patients per protocol (i.e., outside of a clinical trial) in some of those situations. Repopulation In radiobiology, one of the ways in which radiation can fail to destroy cancer is called repopulation. It means that when radiation kills some cancer cells but leaves many behind, the remaining ones now have access to space in which to expand and access to nutrients and oxygen that the other cancer cells had deprived them of. Paradoxically, the tumor can then grow faster than it ever would have before the treatment. This is sometimes seen with rapidly growing tumors, as some head and neck cancers. They sometimes irradiate those cancers multiple times a day to prevent repopulation. Repopulation is never seen with X-ray (or proton) treatment relatively slow-growing prostate cancers. X-rays penetrate throughout the prostate and kill all the cancer there. If there is any survival of an oxygen-deprived tumor core, it will be killed by the next fraction of X-rays in a day or two. However, Lu-177 emits beta rays that may only penetrate to about 125 cells around each target. Actinium-225 (also sometimes used in PSMA therapy) only kills about eight cells around each target. With such short-range killing, there is a real danger of repopulation if there are insufficient PSMA targets within the tumor. Multiple treatments are usually not given for several weeks, and the tumors may have changed by then. PSMA heterogeneity What we have learned recently is that not only does PSMA expression change over time, but in a given patient, some tumors may express PSMA and some may not. Moreover, even within a single tumor, some cells may express PSMA and some may not. Paschalis et al. looked at the degree of PSMA expression of 60 patients with metastatic castration-resistant prostate cancer (mCRPC). They also looked at tissue samples of 38 of them taken when they were diagnosed with hormone-sensitive prostate cancer (HSPC). To detect the amount of PSMA expressed, they used an antibody stain that attaches to the part of the PSMA protein that lies above the cellular membrane. They rated the tumors “0” if there was no PSMA up to “300” if all cells expressed PSMA. They also performed a genomic analysis, looking for mutations in over 100 genes associated with DNA-repair defects. Among the tumor samples from men with HSPC they found: 42 percent of the 38 men with HSPC had no PSMA at diagnosis — it only emerged later 5 of the 6 HSPC men diagnosed with Gleason score 6 or 7 had little or no PSMA expression at that time About half of 30 HSPC men diagnosed with Gleason score 8-10 had little or no PSMA expression at that time Those who expressed PSMA had a worse prognosis Expression of PSMA varied greatly (heterogeneous) between patients Expression of PSMA varied greatly between biopsy samples from the same patient The higher the PSMA expression in a patient, the greater the amount of PSMA heterogeneity Among the tumor samples from the 60 men with mCRPC they found: PSMA expression had increased from when they were diagnosed with HSPC Half of the tumors with no PSMA at HSPC diagnosis continued to have no PSMA 73 percent expressed PSMA; 27% did not – only 1 of whom had neuroendocrine prostate cancer 84 percent of those expressing PSMA exhibited marked PSMA heterogeneity Heterogeneous patterns were identified: PSMA positive and negative cells interspersed in a single area PSMA-positive islands in a sea of PSMA-negative cells PSMA-positive regions separated by >2 mm from PSMA-negative regions Some metastases wholly PSMA-positive, some wholly PSMA-negative in the same patient Bone and lymph node metastases had similar PSMA expression; liver metastases (none neuroendocrine) had lower PSMA expression Analysis of DNA-repair defects revealed: mCRPC patients with DNA-repair defects had higher PSMA expression HSPC patients without DNA-repair defects were less likely to become PSMA-positive Patients treated with PARP inhibitors were more likely to respond if they were PSMA-positive For validation, in a separate sample of tumors, those with DNA-repair defects were found to have much higher PSMA expression than those without such defects. This was especially true for somatic mutations in BRCA2, ATM, and dMMR. PSMA was downregulated in androgen-independent basalcancer cells (resistant to advanced anti-androgens) and neuroendocrine cells. The significance of this study is that it may explain why about a third of PSMA-avid patients do not respond to Lu-177-PSMA therapy. The emitted beta particles may kill cells within about 125 cells from where they are attached at the PSMA site. Thus, cells that do not express PSMA that are more than 2 mm from a PSMA-avid site will not be killed (see “Repopulation” above). The authors hypothesize that DNA-damage repair defects cause PSMA to proliferate. If they are right, a PARP inhibitor (like olaparib), which has also been found to be effective when there are DNA-repair defects (see this link), may be able to increase the efficacy of PSMA treatment. This is the subject of an ongoing clinical trial. Practical detection of heterogeneity Now that we know that heterogeneity can impact Lu-177-PSMA effectiveness, it behooves us to find a way of determining the degree of heterogeneity without doing a biopsy of every single metastatic site. One way is to give each patient two PET scans, so they could see the sites that exhibited PSMA expression as well as the sites that exhibited high uptake on an FDG PET scan. It is futile to offer PSMA-targeted therapy if there are many sites that show up only on an FDG PET scan but few sites that display uptake of PSMA. It also may be futile to treat patients that show some sites where PSMA and FDG sites do not overlap — “discordant.” On the other hand, where there is a high degree of overlap between FDG and PSMA — “concordant” – the PSMA radiotherapy will kill both cancers simultaneously. Of course, the ideal candidate would display only highly PSMA-avid sites. Thang et al. reported on the survival of 30 patients who were treated with Lu-177-PSMA (who were either high PSMA/low FDG or concordant, compared to 16 patients who were excluded based on lack of PSMA (8 patients) or a high degree of discordant sites (8 patients). All patients were heavily pretreated. Treated patients survived 13.3 months (median) Untreated patients survived 2.5 months (median) It is unknown whether the survival of the excluded patients might have been longer or shorter had they received treatment. It is possible that discordant patients may benefit from sequenced (before or after) or concomitant treatment with: Chemotherapy Immunotherapy — trials of adjuvant Keytruda at UCSF and in Melbourne; trials in Los Angeles, Europe and Australia, Germany, various US sites, and New York of a PSMA/T-cell-recruiting antibody + Keytruda; trial at the University of Pennsylvania and Shanghai of a CAR-T/PSMA therapy Xofigo for bone metastases — trial of a therapy that may include both PARP inhibition — trial in Melbourne Other novel non-PSMA targeted treatments It is possible that such adjuvant treatment may decrease the population of discordant sites, and minimize repopulation effects. Based on this new knowledge, it is recommended that patients who are good candidates for Lu-177-PSMA radiotherapy have both a PSMA PET/CT scan and an FDG PET/CT at around the same time. FDG PET scans are generally covered by insurance; PSMA PET scans are not covered by insurance yet. Editorial note: This commentary was written by Allen Edel for The “new” Prostate Cancer Infolink.
  2. An interesting account by Professor Michael Hofman at the Advanced Prostate Cancer Consensus Conference in Basel, Switzerland recently. He speaks of the Lutetium-177 (Lu-177) treatment his team and others have done or are planning: https://www.urotoday.com/video-lectures/apccc-2019-conference/video/1467-players-brightcove-net2019-09-10-14-49-08.html Below the video is a full transcript - all the words Professor Hofman says in the video. Thanks to Nev and Lorraine
  3. Guest

    LuPSMA 177 clinical trial

    Hi fellow advanced members Appreciate if anyone can assist with advice re this topic. I am 72 yo with advanced metatstis bones only.Over the past 7 years have had a radical, Radiation- 36 treatments, Chemotherapy - Doxetaxel, Enzuletimide and the whole time on Lucrine. Yep pretty well tried them all and with a rising PSA, now 47- still low compared to some I am faced with more Chemo -Cabazataxel. I have the opportunity to join the 177 LuPSMA pilot study ( 30 in Australia - no placebo) and will start tests next week to see suitability? Is there any member who is doing this trial or knows anything about it? One side affect ( generally well tolerated) is dry saliva and tear glands which I would like to know about? Any comments most welcome. cheers Roger
  4. Update Lutetium177 Trial. Peter Mac - Treatment for advanced metastatic prostate cancer. At the start of the trial in February 2016 my PSA level was 86.5, a week ago my PSA level had dropped to 26.3 Prior to the trial - scans showed I had a lot of bony metastases. Comparison of the gamma scans taken after each of the three prior Lutetium177 infusions showed the bony metastases and tumors are progressively shrinking. An accurate determination of just how effective the treatment has been will be carried out in approximately 10 weeks time using a variety of sophisticated Pet Scans. I will post the results. During the course of the trial I found that my eyes, not unexpectedly became quite dry but eye drops have solved this problem. Unlike many others on the trial, I developed quite a sore throat. It has recently been established that this is an oral Thrush infection. I developed a similar problem when on Enzalutamide. It is not an uncommon problem when being treated with Cancer drugs,(as the immune system is compromised) but this can be treated with an over-the-counter pharmacy line. Not unlike most other treatments for Prostate Cancer there are some side-effects caused by the treatment but nothing of a major nature. I am in touch with some others on the trial and from what they have said,my experience (with the exception of the continuous sore throat ) seems to be reasonably representative.
  5. Several of our members have been participating in a clinical trial of Lutetium (Lu 177) being conducted at the Peter MacCallum Cancer Centre in Melbourne, Click here to read an article published in the Australian Financial Review about this clinical trial of Lutetium. A large randomised trial to test this treatment next year will be conducted in 2017.
  6. Xofigo (radium 223) has changed the treatment of prostate cancer metastatic to bone. Xofigo is chemically similar to calcium, so tissues that uptake calcium uptake radium as well. That means principally bone, especially in highly metabolically active sites like bone metastases. Lutetium-177 (Lu-177) is a radioactive substance which scientists have attached to an antibody found on the surface of at least 95 percent of prostate cancer cells and called prostate surface membrane antigen (PSMA). Unlike Xofigo, which only attaches to bone metastases, Lu-177-anti-PSMA attaches to any metastasis — bone, lymph node or visceral. It can potentially treat systemic micrometastases as well. Click on the link to read an interesting article in the New Prostate Cancer Infolink.
  7. The Prostate Cancer Foundation of Australia has posted a video on YouTube of the following talk on Advances in Prostate Cancer (Ga68 PSMA PET/CT Scans) given by urologist A/Prof Henry Woo at Sydney Adventist Hospital on 28 September 2015.
  8. PSMA The big thing in Australian prostate cancer research in 2015 was a little wiggly shape that sits on the wall of a prostate cell - PSMA. In normal prostate cells, PSMA is mostly on the inside of the cell wall. In prostate cancer cells, PSMA moves to the outside of the cell wall. So, if you want to find prostate cancer cells - look for PSMA. Researchers have found a key that locks onto PSMA when it finds it. On the free end of this key they can attach lots of things. PSMA scans One type of thing that is attached to the free end of the key is a thing that will show up on scans. Little bits of iron were the first thing that was tried on the free end of the key. It worked very well for the scan - the iron-ended keys gathered on the surface of prostate cancer cells and they stood out well on x-ray. However, other parts of the body were not happy with so much iron, so researchers looked for other things. The most successful thing to be added to the free end of the key for scanning is a radioactive metal - Gallium-68. A PET-CT scan using Gallium-68 at the end of the key can see much smaller prostate cancers than older technology. Several larger Australian hospitals offer these scans, but patients will find themselves a few hundred dollars out of pocket per scan. We can guess this will change in future if radiographers can show the government that the sharper view will extend life. PSMA treatment The free end of the key can have something attached to treat the prostate cancer cells. Radiation Radiation can kill cells, so putting a radioactive metal at the free end of the key has been tried. Gallium-68 is no good for this because it radiates mostly positrons which cause little damage. Another radioactive metal - Lutetium-177 - has mostly damaging beta radiation, and this is being trialled. Drugs Attaching drugs that kill cancer cells to the free end of the key is a promising approach. In this video, Professor Pamela Russell gives us an end of year report on the research she and her colleagues have done at the Australian Prostate Cancer Research Centre. Her team is particularly looking at attaching chemotherapy drugs to the free end of the key. If this works, instead of flooding the whole body with a chemotherapy like Taxotere (docetaxel), the key has the drug on the free end, and the other end attaches directly to the PSMA on the prostate cancer cell. This delivers most of the drug where it is needed, and spares the rest of the body. The video is 40 minutes long. If you can't clearly hear some of the technical terms Professor Russell uses, member Len Wise had kindly provided Cc (closed captions) of every word. (Click on Cc at the bottom of the video to turn them on/off.) See the video here: http://www.jimjimjimjim.com/video---research-report-dec-2015.html Or http://tinyurl.com/ja2rnkw Or Follow the link to our video list on the front page of: http://JimJimJimJim.com
  9. GALLIUM68 PSMA (Prostate Specific Membrane Antigen) PET/CT SCAN. or BE CAREFUL WHAT YOU ASK FOR. Having recently undergone the above scan due to the alarming rate of my PSA recurrence, and to perhaps qualify for a current Oligometastatic trial in Melbourne, I got, perhaps, more than I bargained for. Hoping to identify possible activity in the para-aortic lymph node region, which has been mentioned since diagnoses (and later ruled unlikely), which then perhaps was able to be treated with targeted radiation. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363885 Indeed, this was found-“Malignant PSMA avid small left common iliac node,” but also “small or tiny left distal common iliac nodes (beneath iliopsoas muscle) {left hip} and enlarged left inguinal {groin} node.” {red italics are my interpretations} Unfortunately, it also identified four other sites of PCa activity in my bones, which puts me right into the metatastic club, not somewhere I wanted to be. I personally am comfortable with what I now know, but suggest that this level of knowledge may not suit all who are travelling this path. The Gallium68 PSMA scan, is, I believe the best tool I have seen for identifying areas of PCa activity with great accuracy, and is not limited to areas of bone degeneration, as is the current bone scan. However, until these areas can be treated in Australia (as in the above trial) as they have been able to in the US for the last 15 years, the knowledge is perhaps, wasted.
  10. An article posted on the ABC news site (12 May 15) has revealed a Gamma Knife Radiation Treatment System is being installed at the PA Hospital. While the article focuses on it's capability to more safely treat brain cancers, it does note the following-"The machine can also be used on benign and cancerous tumours in other parts of the body" Here is the link - http://www.abc.net.au/news/2015-05-12/radiation-machine-will-turn-brain-surgery-on-its-head-oncologist/6463294 EDIT-(2hrs later) Unfortunately, from further research It appears that this machine (as pictured) is not capable of full body treatment, as it is not a full tunnel through the back, so may not be much use for other parts of the body. The Hospital press release does not mention 'other parts' http://www.health.qld.gov.au/metrosouth/news/150512-pah-gamma-knife.asp Geoff.
  11. Found an interesting video by A/Prof Henry Woo of the Sydney Adventist Hospital addressing a local support group on the latest scanning and treatment techniques (recorded October 14), highlighting the great leaps forward in disease imaging occurring at the moment. Aggressive Treatment of Aggressive Prostate Cancer ~ A/Prof Henry WooPublished on Oct 19, 2014 A peek into the cutting edge of treatment for advanced or aggressive Prostate Cancer, with information on the next wave of diagnostic scans about to break. Here is the link- //www.youtube.com/watch?v=g-5NXyKo-t8
  12. Paul Edwards (not a doctor) says: For some time I’ve been wanting to gather together all the bits and pieces in the forum on PET Scans. Whatever you do have a look at the amazing video at the end of this post. A positron emission tomography (PET) scan is an imaging test that uses a radioactive substance called a radiotracer to look for disease in the body. Before carrying out a PET scan, a radioactive medicine is produced in a cyclotron (a type of machine). The radioactive medicine is then tagged to a natural chemical. This natural chemical could be glucose, water, or ammonia. The tagged natural chemical is known as a radiotracer. The radiotracer is then inserted into the patient’s body, normally through a canula which has been inserted into the patient’s arm. When it is inside, the radiotracer will go to areas inside the body that use the natural chemical. For example, the 18F-FDG (fluorodeoxyglucose) is a radiotracer that is tagged to glucose. The glucose goes into those parts of the body that use glucose for energy. Cancers, for example, use glucose differently from normal tissue - so, an FDG PET Scan can show up cancers. The 18F-FDG PET Scan is probably the commonly used PET Scan in hospitals. Because prostate cancer is slow-growing, it does not take up glucose as much as other cancers. For this reason researchers have been looking to develop radiotracers that were more suitable to use for imaging prostate cancer. For several years the 11C-Choline PET scan introduced at the Mayo Clinic has been regarded as leading the way in the imaging of prostate cancer. The major limitation of 11C-Choline is that it has a 20-minute half-life (The half life is the time required for one half of the atoms of a given amount of a radioactive substance to disintegrate). This means that 11C-Choline must be used very quickly after it is produced. For this reason, it must be produced on site very close to where it is administered. Normally radiotracers are produced off site for safety reasons. 11C-Choline has shown limited sensitivity in men with very low PSAs. One study showed a 5% detection rate where PSA levels were less than 1. 18F-Fluorocholine is another radiotracer that has been trialled in Europe and Australia with good results. However, it is less sensitive than 11C-Choline and requires a higher PSA level in order to get an effective image. A PSMA PET scan is one that uses a radiotracer which is targeted to a protein (Prostate-Specific Membrane Antigen) that is found in prostate cancer. There are different types of radiotracers are being developed for PSMA PET Scans. For example, in the United States Johns Hopkins University has developed a 18F-DCFBC radiotracer and Memorial Sloan Kettering Cancer Centre has developed a Zr89-J591 radiotracer. In Australia we are now using a Gallium(Ga68) radiotracer which was developed in Germany. The Gallium PSMA PET Scan produces a sharply defined image at very low PSA levels. Because the Gallium PSMA PET Scan targets the Prostate-Specific Membrane Antigen protruding from the outer membrane of the cancer cells, the radiotracer “lights up” on the PET images showing clearly metastases to lymph nodes as well as to bone. [in my case with a very low PSA of 0.58, the Gallium PSMA PET Scan detected 4 metastases that were not visible on other scans.] Seeing is believing. Memorial Sloan Kettering Cancer Centre has produced an excellent video showing the difference that a PSMA PET Scan makes: http://www.mskcc.org/videos/prostate-specific-pet-scans Whilst radiology oncologists are predicting that the PSMA PET Scan will revolutionise the treatment of prostate cancer, that revolution is some time away. At the moment the technology is still being trialled in Australia. There is limited availability of these scans: only a few hospitals in Australia are offering them. The scans are expensive and are not covered by Medicare.
  13. Had a meeting with Patrick Bowden (rad onc Epworth Melbourne) after MRI due to rising PSA. Result negative, but he offered a PSMA PET scan at Peter Mac in about a month. Hoping this will find the problem. It is a full body scan and shows metabolic activity as against structural change. This is very new and has only been available in Melbourne for 3 weeks as of late Sept 2014
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