Synergy between radiation of metastases and immunotherapy confirmed

[Tall_Allen]

Two clinical trials have now confirmed the abscopal effect in prostate cancer. The abscopal effect occurs when cancer antigens activate the immune system, which then goes on a "search and destroy" mission. Cancer antigens are released into the blood by radiation or chemotherapy.

In one longterm trial, SBRT to bone metastases was combined with Yervoy (ipilimumab or "ipi"). Castration-resistant patients (who'd already had docetaxel) survived longer with the combination than with ipi alone (ipi has no effect on its own).

In a short-term phase 2 trial, Xofigo (radium 223 chloride) was combined with Provenge (sipuleucel-T) in castration-resistant patients. It was found to delay progression compared to Provenge alone.

prostatecancer.news/2016/08...

BTW- This was the first article I ever wrote (12/25/2014) for the New Prostate Cancer Infolink. I decided to self-publish my articles just so that I could easily update them, as I've done here.

[noahware]

Great stuff!

"Cancer antigens are released into the blood by radiation or chemotherapy."

Just to be clear, for those not reading links, a beneficial abscopal effect is not necessarily realized from any and all radiation therapy, correct? My understanding is that docs can reliably pursue this effect only within certain treatment parameters (that are still being researched and refined).

I understand that more localized radiation, and only at certain doses, might be better potential triggers because even though the abscopal effect is real, certain radiation treatments still might have an overall effect of dampening or doing damage to the immune response, rather than triggering it to better respond.

So my understanding is that the effect is not always seen with all standard radiation treatments, and "abscopal" refers only to a potential benefit from localized therapy or focused radio-chemo rather than standard systemic chemotherapy. Is that correct?

[And is "radio-chemo" an accurate descriptor for Xofigo?]

[Tall_Allen in reply to noahware]

Everyone here can read the link. If you can't, let me know.

[6357axbz in reply to Tall_Allen]

TA, do you think this abscopal effect would occur in mHSPCa?

[Tall_Allen in reply to 6357axbz]

Those with more favorable disease characteristics (better liver/kidney function, etc.) had a stronger response, so I would imagine earlier is better. It was also interesting that there was no "oligometastatic effect." That is, those with 5 or fewer bone metastases responded as strongly as those with more than 5 bone metastases.

[Schwah]

Thanks Tall Allen. Does this mean that you know support patients going SBRT to distant mets? I know you always said “why not but no proof it will help”. Now that proof exists right ?

Schwah

[Tall_Allen in reply to Schwah]

This shows a benefit ONLY if immunotherapy is used with it. I have advocated for the combination since 2014, but now there is some actual proof. Interestingly, zapping a single met seems to be futile, and there was no special benefit for oligometastatic treatment. I don't know if it works at all with lymph node metastases. I just added a list of unanswered questions.

[6357axbz in reply to Tall_Allen]

Futile? It seems evidence is growing that MDT (radiation) for oligometastatic patients shows a benefit if all mets are zapped. Is this not the case?

[Tall_Allen in reply to 6357axbz]

By "futile" I mean this: As you can read in the article, that there was no abscopal effect in the trials where just one met was zapped.

There is no "growing evidence," just growing speculation about MDT for oligometastatic patients. You can read about the so-called evidence here:

prostatecancer.news/2020/07...

[6357axbz in reply to Tall_Allen]

I am referring to an article Patrick posted a couple of days ago:

"Metastasis directed therapy (MDT) is increasingly used in castration-sensitive oligometastatic prostate cancer (OPCa) because it prolongs progression free survival (PFS) and androgen deprivation free survival."

pubmed.ncbi.nlm.nih.gov/327...

[Tall_Allen in reply to 6357axbz]

Read the article. It explains why that is wrong.

[6357axbz in reply to Tall_Allen]

I don’t understand. The conclusions of the full article are as follows:

“Conclusions

MDT can result in sustained disease control for 30-40% of patients. In patients who experience progression approximately half are oligorecurrent and possibly amenable to repeat MDT. Patterns of recurrence tend to favor osseous progression. These findings, if validated, have implications for future clinical trial design.”

[Tall_Allen in reply to 6357axbz]

That study is useless (as are most retrospective studies without an active comparator) for patients. In fact, I talked to the lead author (Dr Tran) about it just yesterday. Ask yourself these questions:

• What are they comparing it to?

• What would have happened if they had no MDT?

Dr Tran thought they might have a large enough database to do propensity score matching with patients who had no MDT. It's not a randomized clinical trial, but at least, it's a clue. Look at the exponential curve in my article - do you begin to see the problem?

[Tall_Allen in reply to 6357axbz]

I was talking about this article:

prostatecancer.news/2020/07...

[6357axbz in reply to Tall_Allen]

Good article. Scary curve.

At least several oligos here have elected to have their mets zapped, apparently there is no evidence that will improve overall survival and it’s just the intuitive sense that its good to eliminate those tumors as I have recently decided to do. It sounds like I should talk to my MO about adding Provenge to the mix.

[Tall_Allen in reply to 6357axbz]

I don't blame you. I expect I would do the same in your shoes. It would be impossible to get Keytruda or Yervoy without a clinical trial. So, if you can get Provenge, that would be ideal.

[6357axbz in reply to Tall_Allen]

Trying to get a better understanding before communicating with my MO.

In the 799 person trial the summary states:

“In summary, this study did not meet its primary endpoint of improved overall survival in a population with advanced metastatic castration-resistant prostate cancer. However, we did identify some evidence of antitumour activity with ipilimumab treatment as assessed by prespecified secondary and exploratory endpoints, including reductions in PSA concentration and improved progression-free survival...”

How does that square with your statement above,

“In one longterm trial, SBRT to bone metastases was combined with Yervoy (ipilimumab or "ipi"). Castration-resistant patients (who'd already had docetaxel) survived longer with the combination than with ipi alone (ipi has no effect on its own).”

Thanks

[Tall_Allen in reply to 6357axbz]

In the update of the 799-man trial, it definitely improved survival. Didn't I make that clear in the article?

[6357axbz in reply to Tall_Allen]

I’ve got it now. I was looking for the latest trial report and just now found it under one of the links you provided in your article. What I quoted above was from an earlier report (a different link) on that 799 man trial. The latest update, “Fizazi et al 2.4 years“ is clear on the survival benefit. Good stuff. Thanks

[6357axbz in reply to 6357axbz]

On second reading it seems the conclusions as stated are not consistent. The conclusions state:

“OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher than those in the ipilimumab arm.“

The first sentence says the Ipilimumab arm was best for OS. The second sentence states the OS rates at 3, 4, and 5 yr we’re higher than those in the ipilimumab arm. Don’t those two sentences contradict one another?

[Tall_Allen in reply to 6357axbz]

Again, read my article. It says:

"There was better news after the 799 patients were followed for a longer time. In an update by Fizazi et al 2.4 years later, ipi did increase survival in mCRPC patients, all of whom already had docetaxel, who received a single dose (8 Gy) of radiotherapy (SBRT) to one or up to 5 bone metastases. The effect reversed over time.

• From 0-5 months post-SBRT, survival was 49% worse among those who got ipi

• After 5 months post-SBRT, survival was ⅓ better among those who got ipi"

Does that help?

[6357axbz in reply to Tall_Allen]

I understand the results. I’m just saying it appears Fizazi screwed up writing his summary.

[Tall_Allen in reply to 6357axbz]

I don't think they screwed up anything. The shift over time was very much the point of the entire study. They wrote: "the hazard ratio (HR) changed over time: the HR was 1.49 for 0–5 mo, 0.66 for 5–12 mo, and 0.66 beyond 12 mo."

How could they have been more clear?

[6357axbz in reply to Tall_Allen]

I thought I was clear. I’m not referring to anything in the report other than the conclusions at the very end of the report which I repeat verbatim here:

“Conclusions

In this preplanned long-term analysis, OS favored ipilimumab plus radiotherapy versus placebo plus radiotherapy for patients with postdocetaxel mCRPC. OS rates at 3, 4, and 5 yr were approximately two to three times higher than those in the ipilimumab arm.”

The first first sentence is consistent with the study result. The last sentence, however, contradicts that because it says the OS rates were higher than those in the ipilimumab arm.” It should have said the OS rates were higher than those in the placebo arm.

[Tall_Allen in reply to 6357axbz]

Got it! Yes- that is an error.

[addicted2cycling in reply to Tall_Allen]

As I have previously mentioned, in 2015 my Gleason 10 cryoablation destruction also included the use of my treatment provider's 3 drug immunotherapy injection similar to what he had previously used. His having 40+ years of cryoablation experience along with the belief that the abscopal effect does indeed occur following cryoablation when treating prostate cancer patients AND IS ENHANCED with the use of immuno drugs IS WHAT CONVINCED ME to be a one-off experiment. Only time will tell if I made a wise choice but then again IF I HAD FOLLOWED STANDARD TREATMENT PROTOCOL ????

[ProstateWhisperer]

The abscopal effect is also sometimes observed when combining cryotherapy and immuno drugs. Drs. Gary Onik and Jason Williams have both used this treatment for a few years. They say it doesn't always work but when it does the results are truly remarkable.

[addicted2cycling in reply to ProstateWhisperer]

^^^ I'm am one of those guys by Dr. O.

[Tall_Allen in reply to addicted2cycling]

Which immunotherapy did you guys get?

[addicted2cycling in reply to Tall_Allen]

I am not at liberty to name the 3 drugs used by Dr. O. as per his request but can affirm that 2 have been publicized and APPROVED as effect treatment drugs for OTHER CANCERS with the third being his choice based on results from usage and considering the synergy with the others.

[j-o-h-n in reply to addicted2cycling]

I know there's a reason for not naming the 3 drugs.... but tell us the reason... cause it doesn't sound reasonable not to tell us the reason....If indeed you can't disclose the reason I'll make sure we will not ask you the reason again.

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 08/21/2020 2:52 PM DST

[addicted2cycling in reply to j-o-h-n]

Being a ONE - OFF, *endurance athletic individual (65yo at the time) Gleason 10 + Castration + Cryotherapy + Cypionate Injection (Testosterone bi-weekly) only 5 years into THIS EXPERIMENT remaining clear of the Hemi-Cryo'd large volume GL10 tumor in right half with a minimal recurrence in 2018 of GL6/7 in left half that had been focal cryo'd* IS NOT a total success and thus requires A LONGER PERIOD OF TIME before the drugs are named.

[j-o-h-n in reply to addicted2cycling]

Good Reason.............

Good Luck, Good Health and Good Humor.

j-o-h-n Friday 08/21/2020 4:35 PM DST

[V10fanatic]

I guess I'm a sort of "trial" subject. I had Provenge in June and SBRT to 4 mets in July. Let's see how long I stay kickin'

[Hidden]

Movie about Jim Allison who discovered ipi on Netflix- really interesting

[Papillon2]

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