Thoracic RT for ES-SCLC: decreased pt volume?

[RadOncDoc21]

I have never cured a patient with brain relapse from LD-SCLC (who did not get PCI upfront) with WBRT only.

Has anyone, ever?

My experience has changed my approach.

I was all about SRS with WBRT as a salvage option but I kept seeing too many patients develop multiple mets over a short period of time. I had a few patients present to the hospital in between their scans with new disease in the brain for me to basically push for PCI these days.

I still offer both options but I tend to tread more lightly with SCLC. The patients who received PCI actually ended up having a better quality of life compared to those who needed “salvage WBRT.”

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[medgator]

My experience has changed my approach.

I was all about SRS with WBRT as a salvage option but I kept seeing too many patients develop multiple mets over a short period of time. I had a few patients present to the hospital in between their scans with new disease in the brain for me to basically push for PCI these days.

I still offer both options but I tend to tread more lightly with SCLC. The patients who received PCI actually ended up having a better quality of life compared to those who needed “salvage WBRT.”

I don't understand how people equate this to nsclc, my experience has been similar. A few patients who end up refusing pci either get caught quickly with multiple mets on surveillance imaging, or end up refusing everything altogether, including surveillance, and end up symptomatic within a year (sometimes as an inpatient consult!).

Probably the only thing evicore and I agree on is no srs in SCLC brain mets

 

[Neuronix]

My patients refuse PCI. No matter what I say they straight up don't want it. Good luck getting them to agree.

Still I think reasonable minds can disagree and that's why trial is a good idea.

It's still a really hard randomization for us. Most patients want to pick, and in my experience most patients are very anti-whole brain, especially PCI.

 

[drewdog1973]

I have never cured a patient with brain relapse from LD-SCLC (who did not get PCI upfront) with WBRT only.

Has anyone, ever?

Not sure anecdote is best way to figure this out?

Auperin meta analysis (would not have passed muster in this era due to heterogeneity and quality issues of studies) showed 15% survival without and 20% with. Statistically speaking, some small number of that 15% were cured..

 

[Palex80]

Not sure anecdote is best way to figure this out?

Auperin meta analysis (would not have passed muster in this era due to heterogeneity and quality issues of studies) showed 15% survival without and 20% with. Statistically speaking, some small number of that 15% were cured..

How can you draw that conclusion? The Auperin metaanalysis looked into survival with and without PCI for patients with LD-SCLC (and some mixed cohorts of LD-/ES-SCLC too). You cannot draw any conclusion on the number of patients without PCI who were cured by therapeutic WBRT upon progression with brain mets based on that analysis.

I presume that you are trying to make the following point: By extrapolating the risk of brain recurrence without PCI (which can be something like 40%) and advocating that no patient is cured by therapeutic WBRT, less patients would have survived in the non-PCI arm.

However, you cannot base that assumption on merely the incidence of brain metastases without PCI. You need to look at the patients that developed brain metastases as the sole recurrence. PCI may decrease your incidence of brain metastases from 40% to 20%, but even if we assume that nobody is cured by therapeutic WBRT, PCI does not lead to a 20% survival benefit. Why? Because patients progress at other sites too. They do not necessarily die because of the brain mets which arose because they skipped PCI.

You need to look at brain mets as exclusive type of progression to look at how many lives may be saved by PCI.

 

[RadOncG]

You cannot draw any conclusion on the number of patients without PCI who were cured by therapeutic WBRT upon progression with brain mets based on that analysis.

I don't think that's what they were saying.

I think the point was there are some long-term survivors without PCI so we can't use anecdotal "has anyone seen a survivor?" to justify a treatment.

 

[Palex80]

I don't think that's what they were saying.

I think the point was there are some long-term survivors without PCI so we can't use anecdotal "has anyone seen a survivor?" to justify a treatment.

I never said that there are no long term survivors without PCI.
I said that I've never seen a a patient who did not get PCI, then developed brain mets, got therapeutic WBRT and survived.

Not every SCLC patient without PCI progresses in the brain, "only" 40% do.

 

[Lamount]

A couple of thoughts on PCI

1) PCI should remain the SOC until there are convincing data otherwise.

2) My instincts tell me that PCI likely doesn’t lead to cure. Given how quickly sclc divides, you have to imagine there is a VERY narrow window of time where there are sclc cells in ones brain but few enough to be eradicated by 25 Gy... but it can certainly prolong survival in patients with diffuse microscopic CNS disease

3) For SOME patients with metastatic sclc who get Atezo, the kinetics slows down and I end up treating them to metachronous metastases for a long time, almost like a nsclc patient. Others blow right through it and there is little that can be done. It seems like Atezo dichotomizes patients more than standard chemo... but that is anecdotal

If Atezo goes prime time for LS disease (a la LU 005), I imagine there will be an even stronger push to omit PCI... but I don’t think we are there yet.

 

[Neuronix]

A couple of thoughts on PCI

1) PCI should remain the SOC until there are convincing data otherwise.

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial

Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolon…

www.sciencedirect.com

 

[medgator]

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial

Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolon…

www.sciencedirect.com

Let the NCCN know... The thing is, they do, and therefore guidelines have changed over the years for that set of patients. It's not relevant to the LS population

 

[ProtonElectronNeutron]

 

[Lamount]

Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial

Results from a previous phase 3 study suggested that prophylactic cranial irradiation reduces the incidence of symptomatic brain metastases and prolon…

www.sciencedirect.com

Good to know! Obviously the LS population may be more likely to benefit. Additionally patients receiving Atezo may also benefit more as well, given the better disease control (and that IO works best in extracranial sites).

 

[FrostyHammer]

View attachment 331194

This trial is good, except there are 2 fatal flaws which I am sure Palex would agree with me on:
#1- If SRS for 5-10 mets in other cancers isn't mainstream, why include them for SCLC?
#2- The primary endpoint in this trial is not intracranial PFS, OS, etc. It's a cognitive endpoint. Like the case for NSCLC, don't we need to see first that SRS doesn't change outcomes compared to WBRT before going into the cognition issues?

 

[ramsesthenice]

This trial is good, except there are 2 fatal flaws which I am sure Palex would agree with me on:
#1- If SRS for 5-10 mets in other cancers isn't mainstream, why include them for SCLC?
#2- The primary endpoint in this trial is not intracranial PFS, OS, etc. It's a cognitive endpoint. Like NSCLC, don't we need to see first that SRS doesn't change outcomes compared to WBRT before going into the cognition issues?

Lets go a step further: we don't need another SRS vs WBRT cognition trial. That is not in question. Histology is relevant to oncologic endpoints like disease control.

As to point 1, SRS for 5-10 mets is pretty main stream in some parts of the country. I find it highly questionable for SCLC because its a different beast altogether in terms of natural history.

 

[FrostyHammer]

Lets go a step further: we don't need another SRS vs WBRT cognition trial. That is not in question. Histology is relevant to oncologic endpoints like disease control.

As to point 1, SRS for 5-10 mets is pretty main stream in some parts of the country. I find it highly questionable for SCLC because its a different beast altogether in terms of natural history.

Yes this is exactly what I'm saying in my post above. I think SRS for 5-10 mets may be somewhat mainstream in academia but not at all in the community.

 

[evilbooyaa]

This trial is good, except there are 2 fatal flaws which I am sure Palex would agree with me on:
#1- If SRS for 5-10 mets in other cancers isn't mainstream, why include them for SCLC?
#2- The primary endpoint in this trial is not intracranial PFS, OS, etc. It's a cognitive endpoint. Like the case for NSCLC, don't we need to see first that SRS doesn't change outcomes compared to WBRT before going into the cognition issues?

1. SRS for 5-10 mets is mainsteam in quite a few academic facilities, at minimum, and likely some private places as well.
2. The goal of SRS is frequently to avoid the neurocognitive decline seen with WBRT. Proponents of WBRT state that patients not getting WBRT are at risk for developing neurocognitive decline or dying because of untreated brain metastases. I don't get the hate against a composite end point like neurocognitive failure free survival.

SRS will have higher rates of distant brain failure (or intracranial PFS), just like every other SRS vs WBRT study. OS will likely be similar but we need that to be demonstrated for everyone to stop poo-pooing SRS.

I guess I don't get what the beef is with the trial as written (I have nothing to do with the trial). This is a trial that would increase utilization of radiation with repeat SRS sessions every 3-6 months as necessary while limiting the neurocognitive decline and toxicities seen with WBRT. Trial runners should be applauded by SDN for a trial like this, but instead it's a lot of negative comments.

 

[RadOncDoc21]

1. SRS for 5-10 mets is mainsteam in quite a few academic facilities, at minimum, and likely some private places as well.
2. The goal of SRS is frequently to avoid the neurocognitive decline seen with WBRT. Proponents of WBRT state that patients not getting WBRT are at risk for developing neurocognitive decline or dying because of untreated brain metastases. I don't get the hate against a composite end point like neurocognitive failure free survival.

SRS will have higher rates of distant brain failure (or intracranial PFS), just like every other SRS vs WBRT study. OS will likely be similar but we need that to be demonstrated for everyone to stop poo-pooing SRS.

I guess I don't get what the beef is with the trial as written (I have nothing to do with the trial). This is a trial that would increase utilization of radiation with repeat SRS sessions every 3-6 months as necessary while limiting the neurocognitive decline and toxicities seen with WBRT. Trial runners should be applauded by SDN for a trial like this, but instead it's a lot of negative comments.

When have you ever seen a large group of rad oncs agree on anything!?

 

[Neuronix]

I think NRG CC009 is a great study, and I can't wait to open it. Tough randomization for me though--my patients still hate WBRT no matter how much I sell them on it with hippocampal avoidance and memantine.

Off protocol, I'm becoming one of those people I used to laugh at who will SRS just about anything. Yeehaw. I don't really believe in PCI for LS-SCLC, but I understand the other side of the argument. Glad we have a trial, hope it accrues.

 

[FrostyHammer]

1. SRS for 5-10 mets is mainsteam in quite a few academic facilities, at minimum, and likely some private places as well.
2. The goal of SRS is frequently to avoid the neurocognitive decline seen with WBRT. Proponents of WBRT state that patients not getting WBRT are at risk for developing neurocognitive decline or dying because of untreated brain metastases. I don't get the hate against a composite end point like neurocognitive failure free survival.

SRS will have higher rates of distant brain failure (or intracranial PFS), just like every other SRS vs WBRT study. OS will likely be similar but we need that to be demonstrated for everyone to stop poo-pooing SRS.

I guess I don't get what the beef is with the trial as written (I have nothing to do with the trial). This is a trial that would increase utilization of radiation with repeat SRS sessions every 3-6 months as necessary while limiting the neurocognitive decline and toxicities seen with WBRT. Trial runners should be applauded by SDN for a trial like this, but instead it's a lot of negative comments.

1. See my reply to ramses above. There are many many more centers in the nation where SRS for 5-10 mets isn't mainstream. My point is this: if this is such a major issue with brain mets from other disease sites, then why are we just reflexively assuming it's OK and jumping 1-2 steps in logic by using/extrapolating it in SCLC? Randomized trials aren't good for the most part when there are more than 1 variable. Shouldn't we flesh out the role of SRS in 5-10 brain mets in non-SCLC primaries first?

2. When SRS/WBRT trials have been designed and developed in the past, the FIRST questions to be asked are not cognitive related...it's the most basic question: is survival the same? Once that essential issue is resolved, then only should further work with cognition be done. What's the point in evaluating cognition if the patients die more often? I'll add something else: if you wanted to evaluate cognition with HA-WBRT vs SRS, why are you choosing to evaluate this in SCLC of all cancers? Shouldn't this be evaluated first in a general brain met population first? Aside from PCI trials for obvious reasons, have we ever seen a trial asking a question in SCLC brain mets that hasn't been first corroborated in other histologies first?

I think you answered your own question actually, when you wrote: "OS will likely be similar but we need that to be demonstrated"

Yeah, let's go ahead and demonstrate that first...then worry about other things once we've established that essential detail.

 

[evilbooyaa]

1. See my reply to ramses above. There are many many more centers in the nation where SRS for 5-10 mets isn't mainstream. My point is this: if this is such a major issue with brain mets from other disease sites, then why are we just reflexively assuming it's OK and jumping 1-2 steps in logic by using/extrapolating it in SCLC? Randomized trials aren't good for the most part when there are more than 1 variable. Shouldn't we flesh out the role of SRS in 5-10 brain mets in non-SCLC primaries first?

2. When SRS/WBRT trials have been designed and developed in the past, the FIRST questions to be asked are not cognitive related...it's the most basic question: is survival the same? Once that essential issue is resolved, then only should further work with cognition be done. What's the point in evaluating cognition if the patients die more often? I'll add something else: if you wanted to evaluate cognition with HA-WBRT vs SRS, why are you choosing to evaluate this in SCLC of all cancers? Shouldn't this be evaluated first in a general brain met population first? Aside from PCI trials for obvious reasons, have we ever seen a trial asking a question in SCLC brain mets that hasn't been first corroborated in other histologies first?

I think you answered your own question actually, when you wrote: "OS will likely be similar but we need that to be demonstrated"

Yeah, let's go ahead and demonstrate that first...then worry about other things once we've established that essential detail.

Are you suggesting that we run a trial like this for OS primary endpoint first, and then repeat the exact same trial using neurocognitive failure free survival as a primary endpoint? Or if we ran it for OS as primary endpoint, then that would be sufficient evidence for you to do SRS?

I am grateful that we have forward thinking PIs that skip running 'duh' trials like one that evaluates OS in this population as a primary endpoint.

I'm sure intracranial failure and OS will be secondary endpoints, and if there is a strong signal (even if not statistically significant) of differences in OS, then SRS may give people pause.



Some trials evaluating 5-15+ brain mets vs WBRT (HA preferred) are already ongoing:
Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases - Full Text View - ClinicalTrials.gov - Gondi is the NRG collaborator on this but can't find out what NRG CC# this one is.

ClinicalTrials.gov

clinicaltrials.gov

 

[Neuronix]

Some trials evaluating 5-15+ brain mets vs WBRT (HA preferred) are already ongoing:
Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases - Full Text View - ClinicalTrials.gov - Gondi is the NRG collaborator on this but can't find out what NRG CC# this one is.

ClinicalTrials.gov

clinicaltrials.gov

NCIC CE.7 (Canadian) but you can open under US cooperative groups NRG or Alliance.

 

[FrostyHammer]

Are you suggesting that we run a trial like this for OS primary endpoint first, and then repeat the exact same trial using neurocognitive failure free survival as a primary endpoint? Or if we ran it for OS as primary endpoint, then that would be sufficient evidence for you to do SRS?

I am grateful that we have forward thinking PIs that skip running 'duh' trials like one that evaluates OS in this population as a primary endpoint.

I'm sure intracranial failure and OS will be secondary endpoints, and if there is a strong signal (even if not statistically significant) of differences in OS, then SRS may give people pause.



Some trials evaluating 5-15+ brain mets vs WBRT (HA preferred) are already ongoing:
Stereotactic Radiosurgery Compared With Hippocampal-Avoidant Whole Brain Radiotherapy (HA-WBRT) Plus Memantine for 5-15 Brain Metastases - Full Text View - ClinicalTrials.gov - Gondi is the NRG collaborator on this but can't find out what NRG CC# this one is.

ClinicalTrials.gov

clinicaltrials.gov

I think you are highly overlooking and underestimating the concept of a 'duh' trial. If hippocampal sparing WBRT showed clear cognitive improvements in CC001, then why are they running hippocampal sparing PCI in CC003? Sounds like just as much of a 'duh', right?

A secondary endpoint of OS means jack **** because trials are almost never powered for secondary endpoints, only the primary. If they powered the trial for OS as a secondary endpoint, it's effectively the same thing as having it as a primary endpoint.

To answer your question, look at the trial you cited yourself. Look at the co primary endpoints and tell me that that couldn't have been done in this CC009. There's your 'DUH' for you!

 

[evilbooyaa]

I think you are highly overlooking and underestimating the concept of a 'duh' trial. If hippocampal sparing WBRT showed clear cognitive improvements in CC001, then why are they running hippocampal sparing PCI in CC003? Sounds like just as much of a 'duh', right?

A secondary endpoint of OS means jack **** because trials are almost never powered for secondary endpoints, only the primary. If they powered the trial for OS as a secondary endpoint, it's effectively the same thing as having it as a primary endpoint.

To answer your question, look at the trial you cited yourself. Look at the co primary endpoints and tell me that that couldn't have been done in this CC009. There's your 'DUH' for you!

OK, if your beef is that OS should be co-primary endpoint, then OK. Doing a power calculation on what one would expect is a negative endpoint may be tough.

 

[FrostyHammer]

OK, if your beef is that OS should be co-primary endpoint, then OK. Doing a power calculation on what one would expect is a negative endpoint may be tough.

My beef is that OS should be an endpoint for which the trial should be powered. 100%. If you want to add another endpoint on cognition you're welcome to, but doing it in lieu of OS is not good. Calling it primary or secondary is just a semantics issue but at the end of the day a trial that is not powered for OS (+/- other endpoints) is not adequate. I will again state that assuming equivalence is not a foregone conclusion for small cell. What if patients in the SRS arm fail to keep up with the repeated bouts of salvage SRS or WBRT (which would presumably be higher in SCLC than for other histologies) and experience worse OS?

If it helps you to rationalize how assumptions in seemingly 'duh' issues should not be made, especially with regard to OS, think of RTOG 0617. The trial was powered to detect a higher OS in the 74 Gy arm. Everyone thought, at worst, there would be equipoise. Yet what ended up happening? Anything but 'duh'...

 

[thecarbonionangle]

RTOG 1308 is looking at going to 70 gy with protons vs photons in stage II-III NSCLC while meeting constraints.

some very interesting things from protocol, the constraints:

brachial plexus: V70<3 cc, V74 <1cc. Variation acceptable V75 greater or equal to 0.5 cc

heart V50 <0.03cc, V30<50%, V45<35%

Esophagus: max dose of 74gy <1cc of partial circumference

 

[TheWallnerus]

My patients refuse PCI. No matter what I say they straight up don't want it. Good luck getting them to agree.

Still I think reasonable minds can disagree and that's why trial is a good idea.

It's still a really hard randomization for us. Most patients want to pick, and in my experience most patients are very anti-whole brain, especially PCI.

See this is “wild stuff” as Ed McMahon used to say. I have 100% acceptance of PCI in my SCLC patients. Maybe I could teach a course! “How to win friends and influence lung cancer people.”

 

[medgator]

See this is “wild stuff” as Ed McMahon used to say. I have 100% acceptance of PCI in my SCLC patients. Maybe I could teach a course! “How to win friends and influence lung cancer people.”

Agree, I've seen it go both ways, esp if a family member was a smoker who died of brain mets in which case they are ready to start it yesterday

 

[Lamount]

Agree, I've seen it go both ways, esp if a family member was a smoker who died of brain mets in which case they are ready to start it yesterday

I usually don't have trouble getting people to agree to PCI (edit) or HA-PCI... but I can't seem to get anyone on MAVERICK