Harshad Kulkarni1, Christiane Schuchardt1, AVIRAL SINGH1, Thomas Langbein1 and Richard Baum1
- Author Affiliations
THERANOSTICS Center for Molecular Radiotherapy Zentralklinik Bad Berka Bad Berka Germany
Objectives: The aim of this study was to determine the influence of timing of Lu-177 PSMA radioligand therapy (PRLT) in metastatic prostate cancer (mPC).
Methods: Out of 512 mPC patients restaged due to rising PSA by Ga-68 PSMA PET/CT since April 2013, 224 (mean age 71 years, mean Gleason score 8) received totally 649 Lu-177 PRLT cycles (1 - 9 cycles, 3.5 - 12 GBq Lu-177 PSMA ligand per cycle) and were included in the intention-to-treat analysis. The patients were grouped according to previous therapies for mPC - chemotherapy (n=110) including 2nd line with cabazitaxel (n=20), androgen deprivation (n=206), newer drugs abiraterone (n=91) and enzalutamide (n=79), Ra-223 chloride (n=19) and no previous therapy (n=18). The primary tumor had been previously treated by surgery in 154 and external beam radiation therapy in 151 patients. The median overall survival (OS) was computed. Median follow-up was 16 months (3 - 55). The most frequent sites of metastases were bone (184) followed by lymph node (168), liver (28) and lung (26). Serum prostate specific antigen (PSA) levels were monitored before and after therapy.
Results: Reduction in PSA was observed in 157/224 (70 %) patients; 121/224 patients (54 %) demonstrated a PSA decline by >50 % and the best response was complete remission with undetectable PSA. The median overall survival (OS) in all patients was 27 months. First-line PRLT was associated with the longest OS (median not reached at 55 months, all 18 patients are alive). Chemotherapy-pretreated patients had a significantly shorter survival (median OS 19 months) as compared to chemotherapy-naive patients (38 months, p<0.05). OS was also shorter in patients with previous Ra-223 treatment (17 months). Addition of Abiraterone or Enzalutamide provided a significant prolongation of survival (40 months, p<0.05). On the other hand, prior surgical or radiation treatment of primary tumor had no significant effect on the OS (30 months, p>0.05). In patients demonstrating a PSA decline of > 50% after at least 2 PRLT cycles, the OS was significantly longer (38 months).
Conclusions: Early initiation of Lu-177 PSMA radioligand therapy is effective in metastatic prostate cancer, offering a significant survival benefit. Additional treatment with newer antiandrogen agents Abiraterone or Enzalutamide probably has a synergistic effect in combination with Lu-177 PRLT. PSA response after PRLT predicts a longer OS. Previous chemotherapy (1st or 2nd line) and Ra-223 treatment were associated with a worse prognosis. Randomized controlled studies are required to best determine the place of this agent (for e.g. before chemotherapy) in the management of mPC.
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tango65
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I was thinking the exact same thing. Perhaps the reason patients did worse after chemo was because their disease was generally further along for those patients? Seems logical since most patients don’t do chemo until other treatments fail. I hope that’s the reason since I too did chemo early. Hard to imagine another logical reason that those patients did worse ? Any other thoughts out there ?
The title of the study was: "Early initiation of Lu-177 PSMA radioligand therapy prolongs overall survival in metastatic prostate cancer" and not: "Reduced efficacy of Lu-177 PSMA radioligand therapy after Chemo therapy". The authors think that the Lu177 treatment will work better if not used after everything else has failed. Therefore I think the patients who had a Chemo were treated further along the disease course as Schwah assumed. The authors do not mention a hypotheses why the Lu177 treatment works better before Chemo. Not even in the full text. So the conclusion is: the efficacy is better when used earlier in the disease course.
I was very hopeful about Lu-177 before I began the infusions. Not any longer. I have taken two infusions thus far and my PSA has risen from 16 to 46 in about 3 months. The PSMA PET-CT scan shows an increase in qty and size of tumors all over. And, clinically, I am getting intense pain. So much so that I am going to have to radiate the tumor in my right skull shortly.
What next ?? I am probably going to try Ac-225 or a combination of Lu-177 with Ac-225 in South Africa. Let see what happens.
I too am looking forward to going to South Africa (visited in 2012---tourism) and hope the combination therapy works for me. If it does, some game drives are definitely on Btw, my wife and myself loved the food, especially the steaks and escargot
Have you had your skull radiated before? My husband has mets in his skull too and I have been wondering if radiation is possible in that area. I wish you the best of luck with your future treatments!
The tumor in the right portion of my skull was first detected in January, 2018 but considered erroneously to be benign. In October, 2018, the tumor had grown larger and was now considered malignant and cancerous. But, still there was no pain. In Feb, 2019 (my third PSMA PET-CT scan) showed that the tumor had grown even bigger but no pain as yet.
The pain began in the middle of May, 2019 and kept increasing in intensity. It got so bad that I just had to get rid of the tumor and the pain. Surgery was ruled out. Cutting off my neck would be counterproductive The only really good option was radiation.
Today (7/22/2019) I had my tumor radiated and believe-you-me the pain has already reduced by 50%. I truly hope the pain continues to reduce. I have nine sessions of IMRT left. Each session lasts a total of just 10 minutes or so.
Cheers, MeliaQuinn !!! Thank you for your good wishes. I wish your husband all the very best. Yes, radiation of the skull is not only possible, it is painless. GO FOR IT. Choose a good hospital with excellent radiation facilities, technicians who are experienced in radiation and oncologists who can interpret the findings. All the very best !!!
Cutting our heads off and putting them on new bodies is the best idea I've heard yet. Of course the premium bodies would cost more. Good luck with the Ac-225 if that's the way you go. A vacation to South Africa sounds nice.
I wish you well in your South African travels and with your Actinium treatment there. For what it's worth, we have just returned from Heidelberg where my husband received his second combo treatment of Lu-177 and Ac-225 and where on the day after receiving it the nuclear drs came in and abruptly announced that it wasn't working along with numerous other grim pronouncements (gotta love those Germans!) My husband was considered an ideal candidate for the treatment going in and, initially, it appeared it was working but by the end of the first month his PSA started to rise. Then it tripled in 2 weeks after that. I will give a full report on our forary into radionuclides in a separate post, as well as our experiences at the University of Heidelberg and with its doctors. But relative to this study, my husband would fall into the "received chemo prior to receiving radionuclide treatment" group. I'm not sure if that had any effect on the effectiveness of his treatment or not. But I can say, whatsinaname, without pause, that you and your wife will have far more fun in South Africa than you would in Germany! And I guarantee the food will be better, too! Get a photo of a cheetah or something for us!
Thank you very much, Mohopes, for that extremely interesting and informative post
Sorry to hear that the combo therapy is not working for your husband. But, its great that you are taking it reasonably well. Please write about your experience in Germany. I will be very grateful and am sure will enjoy it with your exciting style of writing
Yes, my wife and myself have been to both South Africa (once) and Germany (three times) on holiday. South Africa, undoubtedly, is the more interesting country but Berlin is a city that I have come to really like. Food wise, South Africa wins hands down. We spent 3 nights (out of our 25 nights in SA) in Shamwari Game Reserve, taking a total of 6 game drives. Fantastic. Phenomenal. Amazing. We got so close up with the twin male cheetah's, we could almost shake hands with them The lions were majestic, the elephants gentle as usual, the dainty giraffes, the zebras........yes, I would like to go back.....treatment or no treatment
Thanks for your post. As you can see, it has enlivened me I live to travel and enjoy life. Cheers and thanks again, Mohopes, I look forward to your post on Germany
As the Lu-177 saga unfolds, the U.S. sponsor of the "Vision" trial, Endocyte, now owned by Novartis, must be pulling their hair out as the playing field is changing day by day......They are spending a lot of money to learn what has already been learned by others several years ago..As these studies by foreign researchers get published, the whole pharmaceutical industry is being turned upside down and taking sole possession of that pot of gold at the end of the clinical trial rainbow becomes far less certain...
So far you can only get a Lu177 treatment in the US within clinical trials. If the VISION trial succeeds, I guess it can only fail when too many patients leave the control group, Novartis will have the only approved Lu177 treatment available in the US. I guess Novartis thinks a fair price for the Lu177 treatment will be $500.000 or more.
I completely agree with you. I believe chemo and Xofigo identify patients with the most advanced disease (most probable a larger tumor load). The message I got was: If you are going to use Lu 17 PSMA treatment, use it at the beginning of the metastatic state and not as a salvage therapy after all other therapies have failed. You and I are an example. We both got all the lymph node metastases gone with only one Lu 177 PSMA treatment. We got treated when the cancer was hormone sensitive and after short periods of ADT.
Good to hear as that is my own situation. I have 68Ga PSMA scan scheduled at UCLA in 2 weeks then my consult is done with the Australia group who will start my Lu treatment if the scan is favorable. I had early chemo following RPT 11 years ago: aggressive early treatment for seminal vesicle involvement. I’m happy to have this addition option at this time. (And to be here for it!)
I don't know for sure. My lymph node metastases have the same size (enlarged) after the treatment than before the treatment. I assume there is scar tissue causing the enlargement.
It was very effective in my lymph node metastases. One Lu 177 PSMA treatment took care of all the metastases according to a Ga 68 PSMA done 6 weeks after the treatment. I got treated 2 months after the diagnosis of the metastases. I was in ADT for about 50 days (lupron and casodex) before the treatment.
GP24 had the same expereince with Lu 177 PSMA. One treatment was enough to treat all his lymph node metastases.
Is it worth trying out the combination of Lu-177 + Ac-225 OR Ac-225 alone, having failed Lu-177 ?? What are the odds of success ?? At least 50% or less ??
I had 6 lymph nodes very positive for Ga 68 PSMA in 2016. Two were located in the pelvis posterior to the rectum. The rest were around the aorta and vena cava up to the renal arteries. Between the pelvis and the renal arteries there were many lymph nodes with low SUVs.. Everything became PSMA negative after the first Lu 177 PSMA treatment. I think the low SUV lymph nodes were also metastases.
I had a positive GSMA-68 on the distal rectal LN (pre-sacral node) as well. SUV was about 3.5, near the cutoff. Stats on that LN are only 1.5% occurrence rate because it's posterior to the rectum. Onc said he thought it was a false-positive but will treat anyyway.
I had nodes psma positive in the same area. RO do not usually irradiate the presacral area. Ga 68 Psma will make them change their approach. The presacral nodes did not show psma after the lu 177 psma treatment, even when they had low suv in the Ga 68 PSMA Pet/Ct. Get that node included in the treatment plan.
Tango, thank you for that info, very good data point. Congrats on the good lu 177 tx result knocking out those nodes. Will make sure RO agrees to treat the PS LN as he said last week. Starting 5 weeks 41Gy IMRT today.
I had also had lymph nodes with very low SUV and it was unclear whether these were mets or not. The Cyberknife RO did not want to radiate just the definite mets and omit the unclear ones. Therefore he refused to radiate the mets. If you added all together you could not classify them as oligometastatic.
I also had a lymph node met near my heart, I always thought this would be a false positive because I could not believe to have distant mets. However, it was no longer visible after the Lu177 treatment, so it was an affected lymph node.
Very sorry to hear that Lu177 doesn't appear to be working for you whatsinaname. I will be having my first Ac225 treatment in Delhi September 5th along with having more of the vaccines made that have kept my cancer at bay for a couple of years now. I am hopeful as I am told the SUV is very good. They also told me though that there is evidence that it appears the treatment is more effective if you are on immunotherapy. I am both Keytruda and APCEDEN vaccines in addition to enzalutimide which for Lu177 sounds good. Maybe it will be the same for Ac225? Will know in a few months.
Interesting fact about the chemo. My husband only did the chemo to get into the "Vision" trial. But his results have been outstanding. He just completed scans last week and all known tumors are still resolved and his PSA is now .10
He just received his 5th injection after the scans. So, far so good. One more treatment left. Also note, he started Xtandi when he entered the trial.
Fair wind, his PSA was 34 in December before he started both. Took Xtandi for the first time for 1 month before 1st injection in January and PSA was 4.30.
Having a good, strong PSMA reading is paramount to having success with Lu-177... The trial spends a lot of money having prospective trial participants tested (scanned) to see if they have the PSMA factor. This can involve travel to a distant city..
I agree and I hope this study will help to get a RCT done of Lu 177 PSMA vs ADT plus chemo or plus enza or abi started after initial diagnosis of metastases.
Rats is spot on....My biggest battles have been trying to get insurance approvals....These trials have gatekeepers and you don't get past them without solid insurance approval......
I agree with a lot of the previous opinions for scheduling treatments. My suggestion: At diagnosis with biopsy or MRI, best to follow with PSMA - PET whether PC extracapsular extension or not to determine best primary therapy - with RP or RT or systemic. Any sign of subsequent biochemical failure (PSA increase >0.2ng/ml) have a PSMA PET again to determine spread of PC. Start with second gen ADT: abiraterone/pred or enzalutamie and then nail it with Lu177 if lesions are PSMA-label avid, perhaps up to 4 or more times.
At the present time this approach is contrary to many specialists and is ridiculously expensive for most of us wherever you go to have the treatment (outside of a trial). There may be other useful treatments especially with those with tumours of a particular genetic persuasion (eg BRCA2 variants) but for these it is early days.... =Rob
I have also run into the "not invented here" syndrome. Three months after my RP (August 2018) my PSA was 0.5. I had a PSMA scan at UCLA in March 2019 as part of their salvage radiation trial after RP. The scan found only one spot at the base of the prostate bed (rectoprostatic fascia) . I just finished eight weeks of radiation therapy at UT Health in San Antonio, TX of the prostate bed with a PSA taken right after completion of 0.13. I asked the radiation oncologist if they had enhanced the radiation on the spot found on the PSMA scan. He said no. His response was that was not the standard of care. The doctors did not believe I needed ADT along with the radiation. So what should I do now in your opinion?
Well this is a real witch's brew and not what most of us wanted to hear. Just like the other day when someone was excluded from Lu177 trial because they had had Xofigo already. Implication was having both may be more than body can take in a lifetime. Correct me if I got the wrong impression. And, laugh out loud, maybe this needs another study. Maybe selection bias at work? If not, those of you just entering the game need to start screaming at your congressmen to really really fast track the Lu177. Oh, they just screwed the 9/11 first responders who are dying of cancer. Good luck with that.
I agree. They should fast track Ga 68 PSMA PET/CT and the Lu 177 PSMA treatment. There is evidence that it could help most patients particularly if used earlier in the disease process.
Thank you, Nalakrats , to encourage all of us not to accept treatments against our feelings and minds! We too had to fight against several Docs until we found the best ones.
Hello Tango, it appears that the general rule of thumb in the treatment of PCa is that each subsequent therapy, or next line treatment, has a lower efficacy then one prior to it (unless genomic analysis is used to direct the selection of therapy). The cancer becomes increasingly more aggressive with each cycle of therapy and the disease burden increases with time as well, so it not unexpected that Lu 177 as first line and in conjunction with hormone therapy results in a good response. The trade offs are the side effects of hormone therapy vs Lu 177. Cheers, Phil
I had a Ga 68 PSMA PET/CT showing metastases in the lymph nodes in August 2016. I started ADT and got treatment with Lu 177 PSMA in October. A new Ga 68 PSMA study showed no metastases in December. The ADT was stopped at that time but my testostrone never recovered and I could not get treatment with testotsterone from any of the MOs I consulted with.
IMO ADT probably should have been continued. Not being able to visualize metastases does not necessarily mean that micometastases are not present - there is a detection limit with Ca 68 PSMA - a minimum of 0.5 - 1.0 ng/ml PSA is needed, I believe. Phil
To continue ADT is the way to castration resistant cancer, the lethal phase of PC. I am in that situation now and I regret I did not get testosterone. The initial plan was to stop ADT if the Lu 177 PSMA took care of the metastases and then check the PSA every month . When the PSA was around 0.4 to 1 do another Ga 68 PSMA and if there were metastases get more treatments with Lu 177 PSMA. It did not work because I could not recover the testosterone and eventually the cancer became castration resistant.
The plan continues to be the same. My PSA is around 0.5 (no metastases according to a Ga68 PSMA PET/CT). When it gets to 1 I'll have another Ga 68 PSMA PET/CT and if there are metastases I'll be treated with SBRT or Lu 177 PSMA. I consulted about this plan with Dr. Morris at the Memorial Sloan Kettering Cancer Center and he agreed with it. He thinks it could add a couple of years.
The idea is to delay as much as possible to become castration resistant and if castration resistant delay as much as possible the use of the new anti androgens and chemo. It is not the SOC but many oncologist think it could prolong life. The SOC is the sure way to castration resistant and heavy mutated cancer impossible to control.
Hello Tango65, I like your strategy and find it technically valid as well. I may regret having started the standard of care ADT+chemotherapy when I was diagnosed in early 2016. I did not have enough time to review the literature and form a different opinion other than that SOC appeared to be the way to go with a very rapidly rising PSA. Since time cannot be reversed, my only choice now is to try and maintain control with a multimodal approach (ADT+metformin+statin+NSAIDs and various phytochemicals) and the use of evolutionary game theory (search Pubmed for references, if interested). I may start abiraterone later this year but will not take the maximum tolerable dose and take according to fixed schedule.
I agree that SOC leads to castration resistance - with each round of therapy, ADT, ADT+chemo, abiraterone, enzalutamide, etc that the PCa becomes progressively more castration resistant and aggressive. When the cancer is placed under extreme selection pressures, sensitive (i.e., to hormone and/or docetaxel) PCa cells succumb and resistant ones remain which “releases” the resistant cells from competition with sensitive PCa cells. The theory is that resistant cells have a metabolic disadvantage relative to sensitive PCa cells and that the presence of sensitive cells suppresses the growth of the resistance cells through competition for resources.
Radium 223 (Xofigo) has been used to suppress the growth of bone metastases but it does not offer control - the kill rate at the locations of metastases is not complete (PMID:30557674) and metastases eventually form at other locations on bones and viscerally. I have asked a medical physicist (my brother) to analyze whether Lutetium 177 will perform the same as Radium 223 with respect to its ability to kill. At the present time I do not think it is possible to kill all PCa cells with radionuclide therapy (but this could change, pending the analysis) and therefore PCa cells that remain will contribute to progression. A potential benefit of therapy with radionuclides is that the population of hormone resistant (castration resistant) cells may be greatly diminished after treatment making hormone therapy effective again.
Have you considered bipolar androgen therapy as per Denmeade?
I should mention that there are sensitizers that can be administered along with radionuclides that may improve the efficacy of the therapy. I hope that I have not spoken out of turn. Regards, Phil
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Btw, my wife and myself loved the food, especially the steaks and escargot 
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