ESTRO 2020

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evilbooyaa

evilbooyaa

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Anyone paying attention to ESTRO 2020 stuff? Following some of it on twitter from the usual suspects suggests some interesting stuff, but don't see anything crazy practice changing, at least yet.
 
Another negative trial on SBRT for bone metastasis

OC-0372 Phase 2 RCT comparing conventional radiotherapy with SBRT in patients with bone metastases

My take: Pain response is probably the wrong endpoint in these SBRT vs. conventional RT trials. It's easier to measure it of course than other endpoints and centrally patient centered, however the true benefit of SBRT lies probably in lower rates of local recurrence and need for retreatment.
 
Sober up

 
evilbooyaa said:
Pelvic LN RT adds hugeeeeee bPFS benefit in POP-RT trial out of India in those with > 20% LN risk per Roach formula. Most patients had a PSMA-PET/CT that was negative prior to treatment.

Click to expand...

Neat. 90+% 8y biochemical control in high risk prostate cancer just by adding in ENI? It's a Christmas Miracle. This easily makes ENI the most powerful therapeutic intervention ever conceived or used in high risk CaP.

Prostate ENI: how it started vs how it's going

O6zYbY4.png
 
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We might have a change in fractionation options (?more?) for prostate cancer....Would be interested to see what Evicore thinks of this.

I've been doing more prostate SBRT, but this is compelling. I sometimes do this with prostate SBRT (prostate to 36.25, if MRI dominant lesion take that to 40 Gy ish)...but this is much stronger evidence for this paradigm with a slower course of treatment.

Just a biochemical benefit for now, but unlike ASCENDE not seeing that toxicity bump.

 
scarbrtj said:
Neat. 90+% 8y biochemical control in high risk prostate cancer just by adding in ENI? It's a Christmas Miracle. This easily makes ENI the most powerful therapeutic intervention ever conceived or used in high risk CaP.

Prostate ENI: how it started vs how it's going

O6zYbY4.png
Click to expand...

90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
 
evilbooyaa said:
90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
Click to expand...

Good point - how much of this improvement over "historical controls" is due to better staging?

It does sort of answer the question of in the PSMA (or Axumin) era, there is strong data to treat the nodes in these cases.
 
evilbooyaa said:
90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
Click to expand...
This requires either 1) suspension of disbelief (across multiple beliefs!) or 2) changing some basic understandings about CaP. There were a bunch of Gl 8+ and T3+ patients and PSA>30 patients in this trial. So doing a good staging scan and irradiating normal pelvis now means this cohort of patients--just with staging and 50 Gy/25 fx ENI--suddenly starts behaving like, or better than, Gl 3+3 PSA<10 PSA-detected CaP patients? Her2+ breast cancer was "bad biology" cancer until Herceptin came along and changed the biology/natural history of the disease. These prostate ENI results mirror that magnitude of change (or more)... ie, here, ENI appears to be changing bad biology Gleason 8 patients into well-behaved biology. ENI was a (mostly) swing & miss in so many things, eg breast cancer. Eg prostate cancer! This study is an outlier, an extraordinary claim, BICEP-2ish, etc etc. Why would one need PSMA to apply these findings? Is PSMA a perfect test w/ ~100% NPV? ENI is not *that* toxic; if ENI really works this well, we shouldn't wait for PSMAing IMHO.
 
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evilbooyaa said:
90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
Click to expand...
This is indeed a valid argument.

However this argument works both ways...

You are saying that PSMA-PET-CT accurately detected patients harboring only MICROSCOPIC nodal disease and allowed only those patients to enter the trial, since patients with PET-positive nodes were excluded from the trial. Indeed, had you not performed the PSMA-PET-CT patients with PET-positive pelvic nodes would not have been picked up if the nodes were not enlarged and would have been treated +/- ENI thus "aiding" the ENI-arm to show a meaningful difference.

However at the same time there are two counterarguments:
1. Patients with PSMA-positive pelvic nodes already have microscopic systemic disease and whether or not you treat pelvic nodes is irrelevant, that systemic disease is still going to hit the patient down the road when ADT is over and diminish any difference of ENI.
2. PSMA-PET-CT ruled out patients with distant metastatic disease, which was not picked up on CT & bone scan. Patients with small bone marrow metastasis or the odd paraaortal node without positive pelvic nodes. Excluding those patients with M1-findings on PSMA-PET enhanced the value of the trial in terms of value of ENI.
 
Aside: if anyone thinks this will move the needle on high risk patients getting XRT/ADT/nodal radiation instead of surgery...then think again. These failure curves are unprecedented, but so is the PSMA pet (as compared to surgical literature).

However, this should be at least a new baseline as which to compare...though cross trial comparison always error prone.

Hopefully UK or somewhere finally randomizes a high risk cohort....
 
evilbooyaa said:
90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
Click to expand...

I wouldn’t read into the absolute value too much. It is encouraging data and does suggest very strongly that ENI in this setting looks better than previous data. But it’s a relatively small study. A lot of people have been doing ENI for all of these patients PET or not. I wouldn’t bet more than a couple dollars on it Offering 90% bPFS at 5 years in larger studies.
 
Palex80 said:
This is indeed a valid argument.

However this argument works both ways...

You are saying that PSMA-PET-CT accurately detected patients harboring only MICROSCOPIC nodal disease and allowed only those patients to enter the trial, since patients with PET-positive nodes were excluded from the trial. Indeed, had you not performed the PSMA-PET-CT patients with PET-positive pelvic nodes would not have been picked up if the nodes were not enlarged and would have been treated +/- ENI thus "aiding" the ENI-arm to show a meaningful difference.

However at the same time there are two counterarguments:
1. Patients with PSMA-positive pelvic nodes already have microscopic systemic disease and whether or not you treat pelvic nodes is irrelevant, that systemic disease is still going to hit the patient down the road when ADT is over and diminish any difference of ENI.
2. PSMA-PET-CT ruled out patients with distant metastatic disease, which was not picked up on CT & bone scan. Patients with small bone marrow metastasis or the odd paraaortal node without positive pelvic nodes. Excluding those patients with M1-findings on PSMA-PET enhanced the value of the trial in terms of value of ENI.
Click to expand...

1. That's not really a counter-argument, is it? If they have PSMA-positive pelvic lymph nodes, they were excluded. This is the exact patient population that, without PSMA-PET, would have been included on this trial.... and the exact patient population that would have shown zero benefit to addition of ENI (precisely for the reasons you mention). I guess I'm failing to see how this countermands my "PSMA-PET is the reason the bPFS is 90%"
2. Sure, identifying cN1 vs cM1 disease doesn't make any difference to my argument.

Both counter-arguments are groups of patients, that, historically, would have been included in these high-risk trials (given issues with bone scan/CT scan for staging). By removing these groups of patients (that most would agree, ENI would have zero benefit), they have found an enriched population that does benefit from ENI.

Not all of these patients have microscopic nodal disease.... but the answer may be somewhere around the range of 95 - 81 at 8-year bPFS, or about 14%. They enrolled people with a >20% risk of LN involvement by Roach Formula (which we all know overestimates LN risk). Is the risk ~14%? Maybe.

Did this entire cohort do better than expected? Yes - even 81% bPFS for high-risk is pretty good. Was that because some proportion of patients were spared local therapy when they had small volume cM1 disease (caught on PSMA-PET that would not have been caught on bone scan/CT C/A/P?).

What would be interesting is, of all the patients they screened, how many had a PSMA-PET that made them ineligible to treatment?


1606773096414.png



Above are the curves from 9413, with a 8-year bPFS of ~30-40%. Even PORT alone looks twice(!) as good as the 'winner' in this trial. Maybe it's the RT dose difference (70.2 conventional vs 68 in hypofx). Maybe it's the PSMA-PET. Maybe it's Maybelline.
 
evilbooyaa said:
1. That's not really a counter-argument, is it? If they have PSMA-positive pelvic lymph nodes, they were excluded. This is the exact patient population that, without PSMA-PET, would have been included on this trial.... and the exact patient population that would have shown zero benefit to addition of ENI (precisely for the reasons you mention). I guess I'm failing to see how this countermands my "PSMA-PET is the reason the bPFS is 90%"
2. Sure, identifying cN1 vs cM1 disease doesn't make any difference to my argument.

Both counter-arguments are groups of patients, that, historically, would have been included in these high-risk trials (given issues with bone scan/CT scan for staging). By removing these groups of patients (that most would agree, ENI would have zero benefit), they have found an enriched population that does benefit from ENI.

Not all of these patients have microscopic nodal disease.... but the answer may be somewhere around the range of 95 - 81 at 8-year bPFS, or about 14%. They enrolled people with a >20% risk of LN involvement by Roach Formula (which we all know overestimates LN risk). Is the risk ~14%? Maybe.

Did this entire cohort do better than expected? Yes - even 81% bPFS for high-risk is pretty good. Was that because some proportion of patients were spared local therapy when they had small volume cM1 disease (caught on PSMA-PET that would not have been caught on bone scan/CT C/A/P?).

What would be interesting is, of all the patients they screened, how many had a PSMA-PET that made them ineligible to treatment?


View attachment 324141


Above are the curves from 9413, with a 8-year bPFS of ~30-40%. Even PORT alone looks twice(!) as good as the 'winner' in this trial. Maybe it's the RT dose difference (70.2 conventional vs 68 in hypofx). Maybe it's the PSMA-PET. Maybe it's Maybelline.
Click to expand...

I have to agree with Evil in that I don’t think these are truest counter arguments, just separate sides of the same coin. For an intervention to work the risk has to be high enough (ie, a decent percentage need to have positive nodes) but can’t be too high (extra prostatic disease has to pelvic only). My interpretation of what Evil implied was using PET might be helping find this sweet spot for either reason.

Getting nit picky, I think that goes farther to explaining why ENI showed a significant improvement to PORT than it does to explaining just how stellar the ENI arm did. This feels a little like ASCENDE RT to me. I believe the overall message but question the absolute magnitude of benefit seen in the experimental arm when viewed in context of the relevant literature and personal experience (I have posted on this numerous times before). Put another way, would anyone use this study to tell their patient they only have a 10% recurrence risk with whole pelvic RT and ADT? If it were that good, even with CT staging this argument would probably be settled already.
 
scarbrtj said:
Neat. 90+% 8y biochemical control in high risk prostate cancer just by adding in ENI? It's a Christmas Miracle. This easily makes ENI the most powerful therapeutic intervention ever conceived or used in high risk CaP.
Click to expand...
I hope I'm not just blind looking at the twitter screen capture but this is a tiny study (about 110 pts per arm to start) with very few evaluable patients past 5 years (35-40 ish) and no graphically represented failures in the pelvic arm past about 5 years. Almost looks like data you would see if you started accruing the pelvic arm 1-2 years later but chose a fixed time point to evaluate all data. The gross data shows 7 total failure events in pelvic arm but there are no failures after about 5.5 years? In principle there should be about 22 fewer evaluable patients at later time points in the PORT arm but not the case. Something not right here.

I think a little Bayesian inference appropriate in this case.
 
evilbooyaa said:
1. That's not really a counter-argument, is it? If they have PSMA-positive pelvic lymph nodes, they were excluded. This is the exact patient population that, without PSMA-PET, would have been included on this trial.... and the exact patient population that would have shown zero benefit to addition of ENI (precisely for the reasons you mention). I guess I'm failing to see how this countermands my "PSMA-PET is the reason the bPFS is 90%"
2. Sure, identifying cN1 vs cM1 disease doesn't make any difference to my argument.
Click to expand...
I think it depends on how you look at it.

Patients entering a trial with ENI having cN0-nodes on CT without a PSMA-PET, who would have been excluded from that trial if they have had PSMA-PET because the PET would have showed avid pelvic nodes, will:
a) benefit from ENI, since treating PET-positive nodes with ENI is still better than not treating those nodes at all (50 Gy to a metastatic node will still produce some bPFS benefit - it may not exterminate all disease, but will prolong time to progression arising from that node)
or
b) not benefit from ENI, since they already harbor systemic microscopic disease which evaporates the role of ENI

Does this make sense to you? Sorry, it's kind of difficult to explain. 🙂
 
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evilbooyaa said:
90% bPFS achievable is likely due to more accurate staging with a PSMA-PET, so if you're treating a lower-risk cohort (no unidentified metastatic disease) then nodal RT does more?
Click to expand...

We have seen close to 90% bPFS in high-risk PCA before --> The Arcangeli trial (probably something like 85% on that graph?).

pubmed.ncbi.nlm.nih.gov

Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial - PubMed

Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

1606817934484.png



Bear in mind, Arcangeli gave only 9 months of ADT and no ENI. Staging was with CT/MRI.
 
Palex80 said:
We have seen close to 90% bPFS in high-risk PCA before --> The Arcangeli trial (probably something like 85% on that graph?).

pubmed.ncbi.nlm.nih.gov

Moderate Hypofractionation in High-Risk, Organ-Confined Prostate Cancer: Final Results of a Phase III Randomized Trial - PubMed

Purpose To report the final results on treatment outcomes of a randomized trial comparing conventional and hypofractionated radiotherapy in high-risk, organ-confined prostate cancer (PCa). Patients and Methods This single-institution, randomized clinical trial, conducted from January 2003 to...
pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov

View attachment 324202


Bear in mind, Arcangeli gave only 9 months of ADT and no ENI. Staging was with CT/MRI.
Click to expand...
Look at that POP RT Tata data/curve more closely. He’s showing zero failures in the ENI arm after 5 years. At 8 years the curve is still at 90-95% freedom from failure. Over the many years’ course of the study there were 7 failure events out of 110 ENI patients with T3/4, Gleason high, PSA 30+, etc, disease. This is significantly different from anything the world has ever seen, even Arcangeli. Or archangels. And in this POP RT trial out of India, were patients not also just CT or MRI staged?
 
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scarbrtj said:
Look at that POP RT Tata data/curve more closely. He’s showing zero failures in the ENI arm after 5 years. At 8 years the curve is still at 90-95% freedom from failure. Over the many years’ course of the study there were 7 failure events out of 110 ENI patients with T3/4, Gleason high, PSA 30+, etc, disease. This is significantly different from anything the world has ever seen, even Arcangeli. Or archangels. And in this POP RT trial out of India, were patients not also just CT or MRI staged?
Click to expand...
Thank you, excellent points. Perhaps follow-up, which is at 51 months according to the abstract, is too short?
 
According to slides they were able to get PSMA in 80% of pts at Tata memorial in a trial that started in 2012. Its one the largest hospitals in India and 70% of the pts are indigent. Will wait for this one to get published, gonna take a gander at that supplement
 
scarbrtj said:
Look at that POP RT Tata data/curve more closely. He’s showing zero failures in the ENI arm after 5 years. At 8 years the curve is still at 90-95% freedom from failure. Over the many years’ course of the study there were 7 failure events out of 110 ENI patients with T3/4, Gleason high, PSA 30+, etc, disease. This is significantly different from anything the world has ever seen, even Arcangeli. Or archangels. And in this POP RT trial out of India, were patients not also just CT or MRI staged?
Click to expand...
No, the bolded is my whole point on this. 80% of these patient's underwent a PSMA-PET/CT.

Palex80 said:
I think it depends on how you look at it.

Patients entering a trial with ENI having cN0-nodes on CT without a PSMA-PET, who would have been excluded from that trial if they have had PSMA-PET because the PET would have showed avid pelvic nodes, will:
a) benefit from ENI, since treating PET-positive nodes with ENI is still better than not treating those nodes at all (50 Gy to a metastatic node will still produce some bPFS benefit - it may not exterminate all disease, but will prolong time to progression arising from that node)
or
b) not benefit from ENI, since they already harbor systemic microscopic disease which evaporates the role of ENI

Does this make sense to you? Sorry, it's kind of difficult to explain. 🙂
Click to expand...

I see where you're coming from now - I do think that the proportion of "gross" PSMA-PET positive disease in the lymph nodes that is controlled with 50Gy in standard fractionation is probably less than 10-20%, at most. And yes, it may prolong time to progression, but at the 8-year time point I would expect any 'partial response' to RT to have caused a rebound in PSA sufficient to break thresholds. But I can see how excluding those patients may have theoretically biased the results the other way - in further favor of ENI. I am skeptical, FWIW.

And for your second point, yes, agreed.

And perhaps these results are so good because they're single-institution? Hard to get cooperative group results to look as good as the single instutition stuff.... I think in most disease sites.
 
Palex80 said:
Thank you, excellent points. Perhaps follow-up, which is at 51 months according to the abstract, is too short?
Click to expand...
I didn't read that, but makes sense as the ENI arm started with ~110 patients but only has about 10 at risk at year 8. And they all got "2-3 years" of AAT according to the protocol. If there are just, maybe, two patients with failure events in the ENI arm at year 6-8 that curve will come close or cross over the non-ENI arm (by year 8) because so few are at risk. Publication or no, it'd be... questionable... to countenance these results as practice-changing data despite the "impressive" p value. But I am a devout medical conservative.
 
radiation said:
According to slides they were able to get PSMA in 80% of pts at Tata memorial in a trial that started in 2012. Its one the largest hospitals in India and 70% of the pts are indigent. Will wait for this one to get published, gonna take a gander at that supplement
Click to expand...

evilbooyaa said:
No, the bolded is my whole point on this. 80% of these patient's underwent a PSMA-PET/CT.
Click to expand...
Yes, pretty... interesting... because, also, in theory, they were doing PSMA PET as far back as 2011. And never called for any PSMAing in the protocol.

ClinicalTrials.gov

clinicaltrials.gov clinicaltrials.gov
 
Palex80 said:
Thank you, excellent points. Perhaps follow-up, which is at 51 months according to the abstract, is too short?
Click to expand...
Is that post ADT? because they said 2-3 years ADT, so real post-AT follow up is 15-27 months, which is much less impressive
 
The pelvic RT curve looks too good to be true. I am skeptical and will wait for publication... even then we have ongoing cooperative group studies still addressing this question..
 
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