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  1. Jim Marshall (not a doctor) said ... A number of our members participated in this first trial of using radioactive Lutetium (Lutetium-177, Lu-177) for men who had already had several other treatments. This is the latest report, quoting the study leader, Michael Hofman at Peter McCallum (PeterMac) in Melbourne. After you read the article, if you want to find out what our members might have said about their Lutetium treatment, go to the Search... box near the top of this page and type: Lutetium ... end Jim https://www.healio.com/hematology-oncology/prostate-cancer/news/online/{4a97c48a-da5c-468d-9b43-1a82912542e5}/targeted-radiation-therapy-yields-high-response-rates-in-metastatic-prostate-cancer The article is not on this site. If you click on the link, you will be taken to a site where we do not control the content. So, please be careful about what you read there, and ask your doctor about anything you read. You may need to subscribe to the site to view the article. If the site is temporarily or permanently unavailable, you may receive an error message.
  2. 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.
  3. Barree

    THERANOSTICS

    THERA-NOSTICS Targeted Theraputic LU177- PSMA -617 DIAGNOSTIC COMPANION GA68-PSMA 11 - Pet/CT PSMA -Many prostate cancer cells have a protein on the surface called PS MA (prostate specific membrane antigen). PSMA 6I7 Ligand is a small peptide (molecule ) with a high binding affinity for PSMA. When injected into the bloodstream it looks for the PSMA exuded on the surface of the prostate cancer cells and bonds to it. This ligand not only bonds to PSMA – it also bonds to Lutetium 177 and Gallium 68 (Ga 68). Gallium 68 is a radioactive isotope. From the time it is made radioactive in the hospital laboratory, it only has a half life of 68 minutes. Lutetium177 is also a radioactive isotope which when made radioactive has a half life of 6.64 days. To determine if you are suitable for Lutetium treatment Firstly a Gallium 68 scan is done Gallium 68 is mixed with the PSMA 11 Ligand, this blend is then injected into the bloodstream. The mixture circulating through the bloodstream is attracted to the protein and starts to build up on the surface of the cancer cel ls (in much the same way as iron filings are attracted to a magnet). If there is no PSMA on the cancer cells – you are NOT considered to be PSMA Avid - the Ligand /Gallium 68 blend will just keep circulating and without any PSMA to adhere to, it will be passed in your urine. When the scan is done – there will be nothing to see – so if you are given a dose of Lutetium 177 / ligand blend it too will do nothing, i t will just pass through the bladder and be excreted with your urine. As the Lutetium177/ Ligand blend will have no PSMA to build up on, you will NOT be considered suitable for treatment with Lutetium177. If you are PSMA avid The Ligand /Gallium 68 blend wi ll keep circulating and be attracted to the protein on the surface of the cancer cells and continue to build up on the surface. This will show up on the scan so the location of the PSMA avid cancer cells can be seen. In this case you maybe suitable for treatment with Lutetium177 but suitability still depends on the results of an FDG scan. Secondly a F18 FDG (Glucose ) scan is done If there is no PSMA on the surface of the cancer cells, the Ga68 scan will show nothing but there could still be cancer present – cancer which is not showing up. This is why it is important to have a F18 FDG (Glucose ) scan. This scan can show cancer which does not exude PSMA and in this case, treatments other than Lutetium 177 would have to be considered. When the two scans do not show prostate cancer in the same position, the scans are considered to be discordant - in which case you are not considered to be a suitable candidate for treatment with Lutetium177 - it just won’t work. When you receive a Lutetium177 injection — it starts circulating through the bloodstream, building up on the protein on the surface of the prostate cancer cells and starts killing the cells beneath the protein. The radiation from this (Lu-PSMA) beta mixture only penetrates about 1mm ,so it will not damage the surrounding non-cancerous tissue. It keeps working flat out for approx 7 and a bit days, and then slowly ceases working over the next few weeks as the radioactivity of the Lutetium177 decays Further Ga68 Scans will show the results of the Lutetium177 treatment.
  4. 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
  5. 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
  6. 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.
  7. 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.
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