Question re Lu177 failure

[Rexwaterbury]

When patients fail Lu177 treatment, are any of the remaining cancer cells Psma positive, or have those all been destroyed. If the former, then a Psma/tcell immunotherapy might possibly still be effective. Correct?

[cesanon]

hmmm good question. I can't wait to see what Tall_Allen has to say about it.

[Ahk1 in reply to cesanon]

Me too.

[cesces in reply to Ahk1]

I suspect lu177 pretty much kills dead all the psma cells. It is one on one radiation after all. A proven killer.

It is likely to do real damage to nearby non-pmsa prostate. But perhaps not so potent there.

So it won't touch non-pmsa tumors. And may not fully kill off elements of other mixed tumors.

Let's see what Ta's analysis has to say. Perhaps someone can ask him to weigh in?

[Tall_Allen]

When any kind of radiation kills cancer cells, they do it by inserting ROS (like hydroxyl radicals) into the cell's DNA. Some are killed immediately, but some enter a quiescent state and don't properly die until they try to divide, and that can be years later - they are effectively dead, like zombies, but they just don't know it yet. So they still have PSMA on the cell surface, and it would show up in a PSMA PET scan.

[tango65]

In my case they were killed pretty fast. I had the Lu 177 PSMA treatment on October 28 2016 and a Ga 68 PSMA PET /CT done on December 9 2016 showed that all the lymph nodes were negative (SUV 0) .

Lu 177 PSMA irradiates the cells from the surface and from the inside of the cells. PSMA is a protein which has a part on the surface of the cells and a part inside the cells. The external part of the PSMA molecule is internalized periodically., if Lu 177 PSMA is attached to the PSMA it could be introduced into cell since the ligand is very small.

[Claud68 in reply to tango65]

That's great! Wat about your PSA two months later? Was it undetectable yet or how long did it take to drop until 0.00? Because the dying cancercells are eliminating their PSA for several weeks. Do you think that the complete elimination can take four months or more?

[AlanLawrenson]

Just a word of warning to PSMA Lutetium-177 patients. My brother did very well after all 4 of his injection. Last one mid Feb 19. PSA and PSMA Pet scan mid year showed PSA less than 1 and one 'doubtful' abnormality on a rib. Come September, he started to have lower abdominal pain. Dr wasn't too concerned as PSA was still low. He went to the States/Canada for 5 week holiday. Returned with pain increasing. PSA over 100. Two weeks later 315, then 440 and in 8 weeks gone from 1 to almost 800. Had Metastatic Spinal Cord Compression which sees him with full leg paralysis. Now he is in palliative care with all therapy withdrawn, other than pain management.

The takeaway from this is PSMA Lu patients should continue to monitor their PSA on a fortnightly bases and respond to any pain by a visit to the oncologist.

In my opinion, PSMA Lu-177 will find its place in due course, but as a dual therapy. I also think ligand J591 will be preferred to J617 (merck) in due course.

[GP24 in reply to AlanLawrenson]

There are clinics which can treat spinal cord compression with radiation or surgery plus radiation so the patient in many cases is able to walk again. Therefore your brother should see a doctor who is experienced in doing this.

[AlanLawrenson in reply to GP24]

It is not quite so easy, considering his perilous condition and essential withdrawal of all medical treatment other than palliative care.

Thanks for the reply.

[cesces in reply to AlanLawrenson]

"also think ligand J591 will be preferred to J617 (merck) in due course."

For what reason?

[AlanLawrenson in reply to cesces]

J591 appears in a trial to yield almost 3 times longer time period between injections.

[cesces in reply to AlanLawrenson]

What causes the delay between injections and why is a delay good?

Or do you mean delays between series of injections?

[AlanLawrenson in reply to cesces]

I mean not keeping a close eye on his PSA after the final Lu injection. If he saw his PSA start to accelerate in mid September, his treatment options would have been extensive at that time. Docetaxel would have been first therapy then.

[AlanLawrenson in reply to cesces]

Overall survival was 40.3 months compared (from memory) of 13.4 months for single J617. The OS of course is somewhat dependent on the condition of the patient cohort at the start of the trial.

[GP24]

Rex,

a Lu177 therapy is not curative. Even if you are a super-responder and no lesions are visible on the PSMA PET/CT any more, you will have a recurrence in about a year or so. This will show PSMA positive lesions again on a PSMA PET/CT. So the Lu177 treatment did not kill all PSMA positive tumor cells there are.

Then you can decide if you want to get another Lu177 cycle or try the Psma/tcell immunotherapy within a clinical trial instead.

[Rexwaterbury in reply to GP24]

Good to know. Thanks . How effective is retreating with Lu177? I would think not as effective as the primary treatment.

[GP24 in reply to Rexwaterbury]

Yes, subsequent cycles are less effective. Even the second cycle can be less effective than the first. But they are beneficial.

[EdBar]

Interesting article that may apply, I plan on discussing this with Dr. Sartor during my next visit.

pcnrv.blogspot.com/2019/12/...

Ed

[Patrick-Turner]

It depends what is meant by Lu177 failure. Usually it means that during 4 standard infusions of Lu177 and straight afterwards, Psa keeps going up, even though PsMa scan before the treatment shows high PsMa avidity or uptake of Ga68+ligand. If Psa goes down from a high value of say 50 to 5 a month after last of 4 infusions, then that's a good response. If it keeps going down for next 6 months to say 0.5, its is a very good response, but then if it slowly comes up to 2 a year later then another PsMa scan can be had and if there is no PsMa avidity, it means Pca cells causing Psa rise may not be affected by any more Lu177, and you have enjoyed what success Lu177 had to offer, and that's not failure. It means the next Pca threat is from mutant Pca cells that may / may not have been present in high numbers when first lot of Lu177 was had.

Whatever treatment follows may be decided by DNA analysis and whether you get another year or more of freedom from threat of progressing Pca is anyone's guess. Research on this is going at Peter Mac in Melbourne about this, I suggest you search for videos by a Dr Hoffman at Peter Mac.

My Psa has continued to reduce well after last Lu177 last May. But I am also on Xtandi, and its not known if the drop is due to Xtandi suppressing / slowing growth of Pca cells than won't die, or cells are slowly dying anyway, when they try to divide.

Patrick Turner.

[addicted2cycling]

ITCandy wrote --- " .... Starting chemo soon to hopefully regain control and be in a much better place by summer.... "

GOOD LUCK !!! ;0)

[Notewell]

Hello

I have recently failed a second course of Lu177 therapy and "my" tumours are very much still PSMA positive. So for a sample of at least 1, it is possible.

[Rexwaterbury in reply to Notewell]

If that is the case, then you may see a benefit from a Psma/tcell immunotherapy, such as Car-T or Regeneron bispecifics, correct?

[Notewell]

On the question of whether Lu177 will kill all PSMA tumour cells, this seems unlikely. Firstly the energy or characteristics of the particles emitted by Lu177 decay are not ideal for causing dual strand destruction of DNA in the tumour cells. Ac225 is much better at dual strand DNA damage, which is why it does a better job of killing both tumours and salivary glands. Also, it is known that repeated cycles of Lu177 therapy tend to have less effect and this is because the cancer mutates to become tolerant of single strand DNA damage

[AlanLawrenson]

I really appreciate your response. If only my brother's medical and support teams were as committed as you to get on top of your terrible disease. I wish you a great outcome.

[immunity1]

Rex, you know some of my experience.

I had 4 cycles of Lu177 in 2017 to treat 7 local mets in pelvis (no bone or LN mets). My PSA continued to go down over this regime from 1.2ng/ml to <0.1. However, 5 months after Lu177 finished, my PSA was up to 1 and 24 months after treatment (with PSA of 60ng/ml) bone mets on pelvis and spine detected on PSMA/FDG PET.

That is, 6/7 of the initial soft tissue lesions 'disappeared' (very low PSMA avidity) on imaging; the treatment appears to 'kill' them.

I may contemplate more Lu177 following my current docetaxel.

All the best. =Rob