Does periolesional edema influence dose prescriptin/fractionation for SRS brain mets?

[scarbrtj]

Mr. Miller has a brain met from NSCLC. Mr. Miller get's SRS.
Mr. Miller gets immunotherapy, since his brain met is still visible in the MRI 4 weeksmonths post SRS.

The interesting question is (who knows if it will ever be answered): what would happen were we to have given immuno at hour 4 after SRS instead of at month 4 after SRS for the uncontrolled-after-SRS brain met patients (includes local failures and CNS progressors). And yes there are some uncontrolled brain met patients after SRS. (I'm specifically talking about PD-L1 expressing NSCLC pts in the case of Keytruda.)

The NCCN says it is "reasonable to hold on treating with radiation to see if systemic therapy can control the metastases." And alls I'm saying is if that's reasonable why is it not reasonable to do both now that we have some data? And having personally (which I'm sure you have too) seen some NSCLC folks have good CNS responses with immuno?

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[Lamount]

Most of these stage III patients had macroscopic disease when entering the PACIFIC trial. Or do all your stage III patients have CR 14 days after completing CRT?

So... assuming he has lung cancer and underwent CRT for his thoracic disease and SRS for brain mets, couldn't you then justify immunotherapy... you know, given how unlikely a CR in the chest would be ;-)?

Literature chess aside, common sense tells us that if I find three dandelions in my back yard and yank them out, it would be foolish to assume that my lawn will be dandelion-free for the rest of the season... even without level 1 to confirm my suspicions.

Absence of evidence is not evidence of absence... and this is especially true when reason is on your side.

Have a great weekend!

 

[evilbooyaa]

OK to answer the original question - Would do single frac for the small one and 27Gy/3 (assuming can meet constraints) for the large one. Would not cover perilesional edema or hemorrhage purposefully, although can be somewhat hard to determine sometimes. Agree to have a very short interval from MRI to treatment in this scenario.

While there is some interest in doing IT alone (and deferring local therapy) mostly in melanoma but a small amount in NSCLC as well, this is not, IMO, the patient to do it on.

For this discussion of whether to give immuno or not - yes you refer the patient to a medical oncologist and they should get re-staged, but if they truly have no other sites of disease outside of the brain I don't think it's unreasonable, after a discussion between the med onc and the patient, to observe and re-stage at intervals prior to 'fully' recommending IT.

 

[FrostyHammer]

There are, depending on the moment in which you take the measurement, 100% measurable lesions after SRS. That is to say, get an MRI the day after SRS, 100% of those SRS'd lesions are still hangin' around. Now 90+% of them are "dead men walking lesions" and doomed to regress... but a fraction aren't. An unpredictable fraction. But send all your SRS patients over the med onc the day after SRS, and if he/she gets an MRI on the patient... "Sir you still have a brain met and I want to give you keytruda."

I'm being completely silly in my analogy but you get the point. There will be some SRS patients well after the SRS who have measurable brain mets and the med oncs will want to give them immuno specifically for the brain mets. We know keytruda works for some NSCLC brain met patients (and has a response rate of x%), and we know SRS works for some brain met patients (and has a response rate of y%). What I have yet to see happen in oncology (has it ever happened?) is when two separate, disparate treatments have been tried in a disease, given response rates "x" and "y" with y being greater, that x+y<y. At worst, x+y=y. But usually, almost always, x+y>y; it's been a rather predictable thing. (You can make this x+y>y argument about WBRT+SRS; but then we get into wholly valid toxicity concerns, risk/benefit ratios etc.)

This is exactly why I personally shun MRIs son early after SRS. I'm very much against that view that the med oncs have, to which you referred, largely because many of them have started not even referring for SRS if they can give immunotherapy. This is sadly wrong, especially for a pt like this. Since when has a response rate of 30% been adequate when you have a modality with a control rate three times that high? Our overoptimism for immunotherapy is creating a dangerous precedent if we still want SRS referrals. Then when the patient fails after SRS and they finally get sent to us for mop-up duty, it's increased in size and the risk for radiation necrosis is much higher... Then who are the ones the med oncs blame for RN?

 

[evilbooyaa]

This is exactly why I personally shun MRIs son early after SRS. I'm very much against that view that the med oncs have, to which you referred, largely because many of them have started not even referring for SRS if they can give immunotherapy. This is sadly wrong, especially for a pt like this. Since when has a response rate of 30% been adequate when you have a modality with a control rate three times that high? Our overoptimism for immunotherapy is creating a dangerous precedent if we still want SRS referrals. Then when the patient fails after SRS and they finally get sent to us for mop-up duty, it's increased in size and the risk for radiation necrosis is much higher... Then who are the ones the med oncs blame for RN?

You're seeing med-oncs not refer their NSCLC patients with brain mets for SRS, and instead unilaterally treating with IT? This is wrong and I would challenge it aggressively in tumor board.

We have one melanoma med-onc who does that and we've given up trying to make him/her see reason, and just document the delays in Rad onc referral in our consult notes.

Deferring SRS when we have no idea how to predict who will fall into the 30% (in NSCLC) to 50% (in Melanoma using dual checkpoint inhibition) off a clinical trial is wrong when we don't have any phase III data suggesting equal efficacy.

 

[FrostyHammer]

You're seeing med-oncs not refer their NSCLC patients with brain mets for SRS, and instead unilaterally treating with IT? This is wrong and I would challenge it aggressively in tumor board.

We have one melanoma med-onc who does that and we've given up trying to make him/her see reason, and just document the delays in Rad onc referral in our consult notes.

Deferring SRS when we have no idea how to predict who will fall into the 30% (in NSCLC) to 50% (in Melanoma using dual checkpoint inhibition) off a clinical trial is wrong when we don't have any phase III data suggesting equal efficacy.

Yes I do and totally agreed. The most devious thing those people do is not even list those cases to be presented at tumor board, as if they seriously believe it's a slam dunk. Blind faith in immunotherapy will warp one's mind...

 

[Palex80]

The NCCN says it is "reasonable to hold on treating with radiation to see if systemic therapy can control the metastases." And alls I'm saying is if that's reasonable why is it not reasonable to do both now that we have some data? And having personally (which I'm sure you have too) seen some NSCLC folks have good CNS responses with immuno?

Because "reasonable" is not enough to justify a treatment when you have no hard evidence that it's superior over standard of care.

I am typing it again: There is not evidence in this situation that immunotherapy will enhance OS or any other meaningful endpoint for the patient.

 

[xrthopeful]

Because "reasonable" is not enough to justify a treatment when you have no hard evidence that it's superior over standard of care.

I am typing it again: There is not evidence in this situation that immunotherapy will enhance OS or any other meaningful endpoint for the patient.

This patient was not included in a clinical trial but there is every reason to believe across MULTIPLE clinical trials that a patient with metastatic disease (how did the cancer get to the brain this is elementary, Watson!) that either immunotherapy or chemoimmunotherapy depending on PD-L1 status will improve OS.

I know that many game changing drugs are hard to come by in Europe. This patient lives in the US.

 

[Palex80]

So... assuming he has lung cancer and underwent CRT for his thoracic disease and SRS for brain mets, couldn't you then justify immunotherapy... you know, given how unlikely a CR in the chest would be ;-)?

Good question.
You have evidence to give immunotherapy in:
a) stage III NSCLC following CRT and not progressing
b) stage IV NSCLC with extracerebral disease de-novo
c) stage IV NSCLC with extracerebral disease progressing

I am not going to go into the details of PD-L1-status cause these differ from county to country according to registration and whether or not the patient receives immunotherapy alone or together with chemotherapy.

Your question is:
If a patient after CRT for thoracic disease:
a) developed brain mets after CRT and then received SRS for the brain mets or
b) had brain mets up front and received CRT and SRS up front

If a: He should have been on immunotherapy already after completing CRT anyway (Durva). If he progressed on Durva with brain mets, Durva should be stopped. He will get SRS and (provided extracerebral no evidence of progression) observation.
If b: Strictly speaking you can't use Durva in this indication, since he was stage IV upfront. It depends on how the drug is registered in your country, you may be able to get it with some argumentation. If the patient is stable after CRT, he had a first line platinum doublet and is stable --> no indication for immunotherapy. If the patient shows signs of progression after CRT, then you can give him second line immunotherapy.

Literature chess aside, common sense tells us that if I find three dandelions in my back yard and yank them out, it would be foolish to assume that my lawn will be dandelion-free for the rest of the season... even without level 1 to confirm my suspicions.
Absence of evidence is not evidence of absence... and this is especially true when reason is on your side.
Have a great weekend!

Have a great weekend too!
I agree with you, that conceptionally it may sound "reasonable". We should however not do all that sound "reasonable". This has been shown in many areas of radiation oncology, when one would think a certain approach is "reasonable", yet exactly this approach failed to show any benefit to the patient.

 

[radoncgrad2019]

This patient was not included in a clinical trial but there is every reason to believe across MULTIPLE clinical trials that a patient with metastatic disease (how did the cancer get to the brain this is elementary, Watson!) that either immunotherapy or chemoimmunotherapy depending on PD-L1 status will improve OS.

I know that many game changing drugs are hard to come by in Europe. This patient lives in the US.

yes, for non-small cell lung cancer, it is clear.

 

[Palex80]

This patient was not included in a clinical trial but there is every reason to believe across MULTIPLE clinical trials that a patient with metastatic disease (how did the cancer get to the brain this is elementary, Watson!) that either immunotherapy or chemoimmunotherapy depending on PD-L1 status will improve OS.
I know that many game changing drugs are hard to come by in Europe. This patient lives in the US.

Name me one trial with stage IV solely in the brain and a survival benefit with immunotherapy on top os SRS.

This has nothing to do with US and Europe. It has to with evidence.

 

[FrostyHammer]

This patient was not included in a clinical trial but there is every reason to believe across MULTIPLE clinical trials that a patient with metastatic disease (how did the cancer get to the brain this is elementary, Watson!) that either immunotherapy or chemoimmunotherapy depending on PD-L1 status will improve OS.

I know that many game changing drugs are hard to come by in Europe. This patient lives in the US.

If there's anything we've learned about patients with metastatic disease over the last few years, it's that they are highly heterogeneous. So beware of extrapolating the results of "multiple clinical trials" to the brain met scenario. There is a reason why drug companies rarely want brain met patients on their stage IV trials...

 

[RadOncDoc21]

Good question.
You have evidence to give immunotherapy in:
a) stage III NSCLC following CRT and not progressing
b) stage IV NSCLC with extracerebral disease de-novo
c) stage IV NSCLC with extracerebral disease progressing

I am not going to go into the details of PD-L1-status cause these differ from county to country according to registration and whether or not the patient receives immunotherapy alone or together with chemotherapy.

Your question is:
If a patient after CRT for thoracic disease:
a) developed brain mets after CRT and then received SRS for the brain mets or
b) had brain mets up front and received CRT and SRS up front

If a: He should have been on immunotherapy already after completing CRT anyway (Durva). If he progressed on Durva with brain mets, Durva should be stopped. He will get SRS and (provided extracerebral no evidence of progression) observation.
If b: Strictly speaking you can't use Durva in this indication, since he was stage IV upfront. It depends on how the drug is registered in your country, you may be able to get it with some argumentation. If the patient is stable after CRT, he had a first line platinum doublet and is stable --> no indication for immunotherapy. If the patient shows signs of progression after CRT, then you can give him second line immunotherapy.



Have a great weekend too!
I agree with you, that conceptionally it may sound "reasonable". We should however not do all that sound "reasonable". This has been shown in many areas of radiation oncology, when one would think a certain approach is "reasonable", yet exactly this approach failed to show any benefit to the patient.

Agree!

It was“reasonable” that more doses of radiation would be beneficial in lung, Esophageal, GBM’s but haven’t shown much value. Prior to PACIFIC, it was “reasonable” to give consolidative chemo in locally advanced lung cancer, same with anal, etc. Prior to these trials, I’m sure med oncs were pumping patients with cancer full of chemo before, during and after definitive treatments because it seemed “reasonable.” It’s reasonable to do extended and maybe involved field radiation to lymphoma patients but we have decreased the fields to involved site now because we are able to do less.

Why don’t we let the data show what’s “reasonable” and not either potentially harm the patient financially or physically?

It’s also “reasonable” to use protons for everything but data hasn’t been able to prove that either.

 

[scarbrtj]

there is no clear indication for immunotherapy in this setting.

You're seeing med-oncs not refer their NSCLC patients with brain mets for SRS, and instead unilaterally treating with IT? This is wrong and I would challenge it aggressively in tumor board.

We have one melanoma med-onc who does that and we've given up trying to make him/her see reason, and just document the delays in Rad onc referral in our consult notes.

Deferring SRS when we have no idea how to predict who will fall into the 30% (in NSCLC) to 50% (in Melanoma using dual checkpoint inhibition) off a clinical trial is wrong when we don't have any phase III data suggesting equal efficacy.

Blind faith in immunotherapy will warp one's mind...

Because "reasonable" is not enough to justify a treatment when you have no hard evidence that it's superior over standard of care.

I am typing it again: There is not evidence in this situation that immunotherapy will enhance OS or any other meaningful endpoint for the patient.

I didn't know I'd cause a kerfuffle by saying "how about some keytruda after the SRS" (if the pt is PD-L1 positive). And I didn't say don't give RT at all; not sure how we got on an immuno-only tangent save for the fact I posted a recent immuno-only brain met study for thought-provocation. I'd say I got that.

Of course I agree SRS as an isolated monotherapy is a standard of care for the OP's patient. But how did it become so? It's 100% certain that there's no "equal efficacy" of SRS and immuno (right now) for brain mets; SRS has much higher response rates. But on the other hand if we were to divide the number of randomized trials of SRS alone (vs no RT and best supportive care) by the number of immuno-only trials (for PD-L1 patients, vs no keytruda and best supportive care)... Hence one can argue doing SRS alone is—from a level 1 EBM standpoint on which some seem to be perseverating—just as good as immuno alone. And I'm not even saying that. I'm saying consider immuno after the RT. One may profitably wager that the med onc who referred the patient is.

To all present: you've got a NSCLC PDL1-expressing brain met. It gets treated effectively. You've got no disease elsewhere. Who's not going to take keytruda merely for the fact that upon CNS or distant recurrence he/she can "type": I never felt immunotherapy was going to enhance any meaningful endpoints for me.

 

[Palex80]

Let's have a look at colon cancer, which is a scenario where surgery/local therapy for metachronous metastatic disease is s.o.c. and done with curative intent (it's certainly "more" curative than resecting/SRSing metachronous metastases in NSCLC).

See?

Patients who at stage III have had chemotherapy and later recur with a metastasis get resection/local therapy and are then observed as standard of care. You can add systemic treatment too, but actually the preferred option is to treat locally and observe. And this is happening in colon cancer, where patients with metachronous metastasis still have a 5 years OS of at least 30%... The higher your OS / curative potential, the more inclined you would be to treat the patient with systemic treatment "prophylactically" in order to achieve that goal, wouldn't you agree?

Oh, and last but not least: We are talking about colon cancer, where 90% of metachronous metastases are liver or lungs. Both of them, sites where systemic treatment works well. A lot better than then 30% response rate of Keytruda in the brain.

 

[Lamount]

[

Good question.
You have evidence to give immunotherapy in:
a) stage III NSCLC following CRT and not progressing
b) stage IV NSCLC with extracerebral disease de-novo
c) stage IV NSCLC with extracerebral disease progressing

I am not going to go into the details of PD-L1-status cause these differ from county to country according to registration and whether or not the patient receives immunotherapy alone or together with chemotherapy.

Your question is:
If a patient after CRT for thoracic disease:
a) developed brain mets after CRT and then received SRS for the brain mets or
b) had brain mets up front and received CRT and SRS up front

If a: He should have been on immunotherapy already after completing CRT anyway (Durva). If he progressed on Durva with brain mets, Durva should be stopped. He will get SRS and (provided extracerebral no evidence of progression) observation.
If b: Strictly speaking you can't use Durva in this indication, since he was stage IV upfront. It depends on how the drug is registered in your country, you may be able to get it with some argumentation. If the patient is stable after CRT, he had a first line platinum doublet and is stable --> no indication for immunotherapy. If the patient shows signs of progression after CRT, then you can give him second line immunotherapy.



Have a great weekend too!
I agree with you, that conceptionally it may sound "reasonable". We should however not do all that sound "reasonable". This has been shown in many areas of radiation oncology, when one would think a certain approach is "reasonable", yet exactly this approach failed to show any benefit to the patient.

this reminds me of a debate that I would frequently have with one of my mentors during training. I would argue that the literature helps provide insight into the best course of treatment. He would argue that the literature defines the best course of treatment.

I respect the purists point of view, but in my heart of hearts I think a true purest would find that the literature fails to provide a definitive recommendation for most of his/her patients. Example: stage III NSCLC, PDL1 <1% (not uncommon in my practice)... do you give adjuvant durva? There were patients included on the winning are with PDL 1 <1%. Indeed, subgroup analysis with PDL 1 < 25% shows an overall survival benefit... but a subsequent subgroup looking at <1% does not have OS benefit. Is this because patients with less than 1% don’t benefit or is this because there wasn’t enough power In that subgroup to show a difference? shouldn’t we just ignore this sub group analysis entirely since it was conducted post hoc?


Does inclusion of a certain population of patients on a clinical trial mean that all patients in this population should receive the winning arm of the trial? Does lack of inclusion of a certain population on that trial mean that the results cannot be applied?

There are no data to answer these questions, only logic and reason can provide guidance.

The relevant questions for our conversation are

1) Do patients who present with brain metastases as the only site of metastatic disease only die from their brain metastases, or do extra cranial failures contribute a significant amount of mortality?

As demonstrated here, patients with brain only metastases that are treated with SRS are more likely to die from extracranial failure than intracranial failure.

2)Is the impact of extracranial failure on mortality enough to justify a systemic treatment?

I believe so, given that the median survival in the study 1.5 years, indicating outcomes aren’t great in those brain-only metastases... and a pleurality if these patients died from extracranial failure

3)Do we have any reason to believe that immunotherapy would be less effective in preventing distant failure in patients who present with brain-only metastases as compared to those who present with extracranial metastatic disease?

not to my knowledge


In my approximation, there are multiple ways to view the literature. But I don’t think it’s any more defensible to assume the omission of patients with brain metastases from the studies justifies not using immunotherapy than it is to assume immunotherapy does have a role for the reasons I’ve presented above.
**Edited to fix the quote

 

[RickyScott]

Because "reasonable" is not enough to justify a treatment when you have no hard evidence that it's superior over standard of care.

I am typing it again: There is not evidence in this situation that immunotherapy will enhance OS or any other meaningful endpoint for the patient.

Absence of evidence is not evidence of absence and risk asymmetry comes into play here. Immunotherapy is not very toxic and 90% of these pts will develop more disease and it is not unreasonable to believe any systemic therapy works best when disease burden is lowest.

 

[FrostyHammer]

Do we have any reason to believe that immunotherapy would be less effective in preventing distant failure in patients who present with brain-only metastases as compared to those who present with extracranial metastatic disease?

I agree with you on the distant failure part, but we do know that immunotherapy is less effective in preventing local failure of existing mets if those mets are intracranial. Simply can't penetrate adequately. As you know, local failure is a major cause of death in brain met patients. Moreover, there are plenty of data showing worse survival with brain mets as compared to other sites - this is why drug companies don't want these pts on trials (along with ECOG 2+, etc). Gotta have a good prognosis to enjoy the benefits of immunotherapy, and the drug companies know it like the back of their hands.

 

[RadOncDoc21]

I recommend we start doing annual screening PET scans for everybody along with brain MRI’s and to initiate prophylactic immunotherapy at birth. The best way to beat cancer is to screen and treat for all of them before you get any!

 

[scarbrtj]

I recommend we start doing annual screening PET scans for everybody along with brain MRI’s and to initiate prophylactic immunotherapy at birth. The best way to beat cancer is to screen and treat for all of them before you get any!

You said in theory we all have cancer cells. (Or at least maybe we have cells always on the cusp of becoming cells we recognize as cancer cells; I actually concur.) Those robbed of "prophylactic immunotherapy at birth" certainly may need increased screening for their higher cancer rates. Of course right now in medicine there's no anti-cancer immunotherapy offered at birth. But it's close!

 

[radoncgrad2019]

I recommend we start doing annual screening PET scans for everybody along with brain MRI’s and to initiate prophylactic immunotherapy at birth. The best way to beat cancer is to screen and treat for all of them before you get any!

yes because this is exactly the same thing that Lamount and others said

this sort of straw man argument doesnt serve you well

 

[RadOncDoc21]

yes because this is exactly the same thing that Lamount and others said

this sort of straw man argument doesnt serve you well

This “strawman’s” data is just as good as yours.

 

[RickyScott]

I agree with you on the distant failure part, but we do know that immunotherapy is less effective in preventing local failure of existing mets if those mets are intracranial. Simply can't penetrate adequately. As you know, local failure is a major cause of death in brain met patients. Moreover, there are plenty of data showing worse survival with brain mets as compared to other sites - this is why drug companies don't want these pts on trials (along with ECOG 2+, etc). Gotta have a good prognosis to enjoy the benefits of immunotherapy, and the drug companies know it like the back of their hands.

Why does immunotherapy need to penetrate the brain. Keytruda is just binding to pd1 on tcells (treg?)? I am sure it is not that simple, but cns “penetration” seems fine in melanoma.

 

[FrostyHammer]

Why does immunotherapy need to penetrate the brain. Keytruda is just binding to pd1 on tcells (treg?)? I am sure it is not that simple, but cns “penetration” seems fine in melanoma.

Because T cells themselves have to be able to cross the BBB. This is no easy task - recall this is why brain mets are by far best dealt with using EBRT - however, remember that this is leaky in brain mets, so all hope isn't lost. Nevertheless, the interaction with PD1 and PDL1 happens in the tumor stroma once the BBB is crossed. If an immunotherapy drug doesn't cross the BBB well itself, then it's hard for the T cell it's latched onto to cross the BBB too, right? Or, if it crosses the BBB on its own and meets the T cell in the tumor stroma, rather the being pre-latched onto it, still requires it to have independent BBB penetrability.

 

[Lamount]

I agree with you on the distant failure part, but we do know that immunotherapy is less effective in preventing local failure of existing mets if those mets are intracranial. Simply can't penetrate adequately. As you know, local failure is a major cause of death in brain met patients. Moreover, there are plenty of data showing worse survival with brain mets as compared to other sites - this is why drug companies don't want these pts on trials (along with ECOG 2+, etc). Gotta have a good prognosis to enjoy the benefits of immunotherapy, and the drug companies know it like the back of their hands.

If medical oncology deferred systemic therapy in anyone with a poor prognosis, they would lose 90% of their patients.

immunotherapy is first line systemic therapy for metastatic nsclc. If anything it has a greater role in poor PS patients as it is as IO mono therapy easier to tolerate than most “light” chemo.

regarding IO and the BBB, I agree that it is not super effective. Fortunately, we have EBRT. But the paper I cited several posts ago shows that extracranial failure is a significant driver of mortality in patients NSCLC with brain-only mets treated with SRS.

my point to Palex is that failure to include brain-only mets patients in IO trials doesn’t mean they shouldn’t get IO... Especially when there are data demonstrating that these patients are at significant risk for mortality from extra cranial failure -just like other metastatic patients.

 

[PhotonBomb]

If medical oncology deferred systemic therapy in anyone with a poor prognosis, they would lose 90% of their patients.

immunotherapy is first line systemic therapy for metastatic nsclc. If anything it has a greater role in poor PS patients as it is as IO mono therapy easier to tolerate than most “light” chemo.

regarding IO and the BBB, I agree that it is not super effective. Fortunately, we have EBRT. But the paper I cited several posts ago shows that extracranial failure is a significant driver of mortality in patients NSCLC with brain-only mets treated with SRS.

my point to Palex is that failure to include brain-only mets patients in IO trials doesn’t mean they shouldn’t get IO... Especially when there are data demonstrating that these patients are at significant risk for mortality from extra cranial failure -just like other metastatic patients.

You’re making too much sense for these folks

 

[evilbooyaa]

I think most people are going around in circles here. I don't think anyone is advocating for IT alone in this scenario. I think everyone agrees at least SRS. The question is whether to add IT afterwards in someone who does not have evidence for extracranial metastatic disease.

If it were me, I'd want the Keytruda after completing SRS (and maybe pushing for resection of the large hemorrhagic met). I know I don't have a phase III clinical trial in only my specific patient population to justify IT use, but I certainly don't think it's reasonable.

That being said, Palex is technically (which is the best kind!) right, that there is no phase III data for patients in this scenario.

Palex, I don't believe in the parallel to colon cancer honestly. Prior chemotherapy generally means that they got neoadjuvant chemotherapy prior to resection (not adjuvant chemotherapy used at time of their localized disease). As you can see from the top portion of your figure, if you get upfront resection, you go on to get systemic therapy, which is what most are advocating here (SRS analogous to resection, IT analogous to chemotherapy).

 

[radiation]

An implied argument in this case, and many cases in cancer, is if there is a measurable difference in upfront vs. salvage therapy. Will there be a difference in outcomes if you treat assumed microscopic systemic upfront vs. waiting to initiate at macroscopic progression? This argument manifests itself in many forms - post op prostate, PCI in small cell, etc. Some of this is practical - if the pt doesn't have any measurable extracranial disease, how long do you give IO (12 months per PACIFIC?). If they recur during or after IO does that mean IO doesn't work and you shouldn't give more after? Does IO work better in the adjuvant setting or does it require a threshold of tumor antigens to stimulate a response? Sounds like this is an area of equipoise as we wait for more data

 

[scarbrtj]

An implied argument in this case, and many cases in cancer, is if there is a measurable difference in upfront vs. salvage therapy. Will there be a difference in outcomes if you treat assumed microscopic systemic upfront vs. waiting to initiate at macroscopic progression? This argument manifests itself in many forms - post op prostate, PCI in small cell, etc. Some of this is practical - if the pt doesn't have any measurable extracranial disease, how long do you give IO (12 months per PACIFIC?). If they recur during or after IO does that mean IO doesn't work and you shouldn't give more after? Does IO work better in the adjuvant setting or does it require a threshold of tumor antigens to stimulate a response? Sounds like this is an area of equipoise as we wait for more data

Am I correct in thinking that 4+ year old QUARTZ was the last randomized brain met/RT trial we have. (And what a helpful trial it was!) Sadly very little we can argue about based on great data. Meanwhile, about maybe 50% of the SRS only patients are going to have another CNS event (whether LF or CNS progression) over the next 12 months. But we say, correctly, "there's no randomized data that anything else should be done." How lazy we have been, and are, about studying such a common clinical presentation. Young rad oncs could really make a splash in this arena IMHO vs figuring out how to get breast RT down from five fractions to four.

 

[PhotonBomb]

This is the most recent major SRS Brain mets trial published, want to say more recent than Quartz

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial - PubMed

National Cancer Institute.

pubmed.ncbi.nlm.nih.gov

This the most recent Brain mets randomized trial

https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.2009

The reason we won’t have randomized data for that specific question btw is because no one in their right mind is going to not give systemic therapy to the patient with Brain mets who is able to get systemic therapy and has not seen immunotherapy before.

What an idiotic thread this is becoming

 

[RadOncDoc21]

This is the most recent major SRS Brain mets trial published, want to say more recent than Quartz

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial - PubMed

National Cancer Institute.

pubmed.ncbi.nlm.nih.gov

This the most recent Brain mets randomized trial

https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.2009

The reason we won’t have randomized data for that specific question btw is because no one in their right mind is going to not give systemic therapy to the patient with Brain mets who is able to get systemic therapy and has not seen immunotherapy before.

What an idiotic thread this is becoming

God-Forbid anybody who challenges your stong claims with (or lack of) supportive data.

I guess in your system it’s whoever screams the loudest or calls each other names gets to do whatever they want to the patient.

 

[FrostyHammer]

If medical oncology deferred systemic therapy in anyone with a poor prognosis, they would lose 90% of their patients.

immunotherapy is first line systemic therapy for metastatic nsclc. If anything it has a greater role in poor PS patients as it is as IO mono therapy easier to tolerate than most “light” chemo.

regarding IO and the BBB, I agree that it is not super effective. Fortunately, we have EBRT. But the paper I cited several posts ago shows that extracranial failure is a significant driver of mortality in patients NSCLC with brain-only mets treated with SRS.

my point to Palex is that failure to include brain-only mets patients in IO trials doesn’t mean they shouldn’t get IO... Especially when there are data demonstrating that these patients are at significant risk for mortality from extra cranial failure -just like other metastatic patients.

First statement: agree, but this is in context of palliative chemo, not multimillion immunotherapy compounds that really need to be thought through before they're given. Financial toxicity is real. Disagree that it has more utility in pts with worse PS. All the data that immunotherapy is built on, all the advantages, all the promise, is in better prognostic patients. If your argument is true (together with your last point), we should give immunotherapy willy-nilly to everyone in place of chemo right now just because it's nearly always going to be better tolerated than chemo regardless of disease site. But alas, because of data and evidence there is some level of order in the onco-universe without which we'd all descend into chaos. There just simply have to be limits - limits of what is known.

Understand your third point, not incorrect.

 

[PhotonBomb]

‘we should give immunotherapy willy-nilly to everyone in place of chemo right now just because it's nearly always going to be better tolerated than chemo regardless of disease site.’

No. That’s not what anyone is saying. What we are saying is that for non-driver mutation NSCLC there are multiple positive trials for OS either with monotherapy, chemoimmunotherapy,
Or combined checkpoint inhibition

 

[FrostyHammer]

‘we should give immunotherapy willy-nilly to everyone in place of chemo right now just because it's nearly always going to be better tolerated than chemo regardless of disease site.’

No. That’s not what anyone is saying. What we are saying is that for non-driver mutation NSCLC there are multiple positive trials for OS either with monotherapy, chemoimmunotherapy,
Or combined checkpoint inhibition

100% agree with you. The point I was making above was in response to Lamount using the improved tolerability as justification for using immunotherapy in the absence of data or adequate representation in randomized trials (the poor PS topic above). This is incorrect. The justification to use immunotherapy is adequate representation of patients from positive randomized trials. Most anything else is asking for financial toxicity and making the drug companies gleeful.

 

[Palex80]

Palex, I don't believe in the parallel to colon cancer honestly. Prior chemotherapy generally means that they got neoadjuvant chemotherapy prior to resection (not adjuvant chemotherapy used at time of their localized disease). As you can see from the top portion of your figure, if you get upfront resection, you go on to get systemic therapy, which is what most are advocating here (SRS analogous to resection, IT analogous to chemotherapy).

I am sorry, but that is incorrect.

According to guidelines, resecting a metachronous resectable colorectal metastasis without giving systemic therapy is perfectly fine.

Here are two quotes from the German-speaking S3-guideline

They read:

"Neoadjuvant chemotherapy of primary resectable liver metastases should not be carried out"

"Adjuvant/additive chemotherapy after resection of metastases should not be carried out"

Grade of recommendation is B, with a level of evidence 2a/2b respectively.



The ESMO guidelines are a little more vague, but still advocare for primary resection without systemic treatment:

So you get only get better DFS but not better OS through adding chemotherapy perioperative.

 

[Palex80]

The reason we won’t have randomized data for that specific question btw is because no one in their right mind is going to not give systemic therapy to the patient with Brain mets who is able to get systemic therapy and has not seen immunotherapy before.

What an idiotic thread this is becoming

We have numerous patients which do not get immunotherapy in this scenario.

We probably have 5 patients per year presenting with an early disease NSCLC (stage I) primary in the lung and a solitary brain met.
Standard of care is to resect or ablate both.
None of these patients gets chemotherapy or immunotherapy if after local treatment, no further tumor manifestation is detected.

Bear in mind this only applies to patients with an early stage primary tumor. Those who present with N1/N2, get systemic treatment.
But the ones with small peripheral 2cm primary N0, simply get resection/ablation for lung and brain.

The algorithm is also different for those presenting with adrenal metastasis. These patients get systemic treatment too, regardless of their disease stage in the lung.


And now, here's what NCCN says for the lung.

It merely says "consider" systemic treatment. Nowhere is it a "must".

Simply because the data is not there.

 

[RadOncDoc21]

We have numerous patients which do not get immunotherapy in this scenario.

We probably have 5 patients per year presenting with an early disease NSCLC (stage I) primary in the lung and a solitary brain met.
Standard of care is to resect or ablate both.
None of these patients gets chemotherapy or immunotherapy if after local treatment, no further tumor manifestation is detected.

Bear in mind this only applies to patients with an early stage primary tumor. Those who present with N1/N2, get systemic treatment.
But the ones with small peripheral 2cm primary N0, simply get resection/ablation for lung and brain.

The algorithm is also different for those presenting with adrenal metastasis. These patients get systemic treatment too, regardless of their disease stage in the lung.


And now, here's what NCCN says for the lung.


View attachment 302109

View attachment 302110


It merely says "consider" systemic treatment. Nowhere is it a "must".

Simply because the data is not there.

Stoopid science and evidence-based medicine recommendations. It should only be based on what some people feel is right!

 

[PhotonBomb]

Yes agree that a stage 1 with a solitary BM get definitive treatment of each, that would be one where people are mixed on whether they give a few cycles of systemic or not, but I agree that would be the one situation in which I would not strongly advocate for systemic therapy.

 

[Lamount]

We have numerous patients which do not get immunotherapy in this scenario.

We probably have 5 patients per year presenting with an early disease NSCLC (stage I) primary in the lung and a solitary brain met.
Standard of care is to resect or ablate both.
None of these patients gets chemotherapy or immunotherapy if after local treatment, no further tumor manifestation is detected.

Bear in mind this only applies to patients with an early stage primary tumor. Those who present with N1/N2, get systemic treatment.
But the ones with small peripheral 2cm primary N0, simply get resection/ablation for lung and brain.

The algorithm is also different for those presenting with adrenal metastasis. These patients get systemic treatment too, regardless of their disease stage in the lung.


And now, here's what NCCN says for the lung.


View attachment 302109

View attachment 302110


It merely says "consider" systemic treatment. Nowhere is it a "must".

Simply because the data is not there.

If, in your heart of hearts, you believe that the risk of extracranial failure does not justify systemic therapy in a patient with NSCLC who has already developed brain metastases... Following SRS, I can understand why you choose to observe.

However, if you do indeed acknowledge the data showing that these patients don't live long, and more commonly die from extra-cranial failure than other causes, and you are deferring IO merely because of a whole in the RTCs... I would disagree with your reasoning.

Out of curiosity, in your experience, how have patients treated with this approach fair? Are they NED > 1-2 years?

 

[scarbrtj]

We have numerous patients which do not get immunotherapy in this scenario.

We probably have 5 patients per year presenting with an early disease NSCLC (stage I) primary in the lung and a solitary brain met.
Standard of care is to resect or ablate both.
None of these patients gets chemotherapy or immunotherapy if after local treatment, no further tumor manifestation is detected.

Bear in mind this only applies to patients with an early stage primary tumor. Those who present with N1/N2, get systemic treatment.
But the ones with small peripheral 2cm primary N0, simply get resection/ablation for lung and brain.

The algorithm is also different for those presenting with adrenal metastasis. These patients get systemic treatment too, regardless of their disease stage in the lung.


And now, here's what NCCN says for the lung.


View attachment 302109

View attachment 302110


It merely says "consider" systemic treatment. Nowhere is it a "must".

Simply because the data is not there.

This is all interesting and well and good about Stage I lung. And colon cancer etc.
But our OP said 'twas a lung adeno, diagnosed a while ago, treated with chemo in past, and had brain mets in 2017 and had SRS. Now he has new brain mets. My guess is his chance of having brain mets again in the future after SRS alone is ~90% (if he lives a year or two). There is an old saying, I'm sure you've heard it: brain mets present a high risk to a patient's health and well-being. (A new spot in the brain presents different problems than a new spot in the liver e.g.) This patient faces that 90+% recurrence risk in spades I'm afraid even if this second SRS go-'round is perfect. So here is my very limited, very particular, don't-care-about-non-CNS-systemic-disease point:
1) After SRS alone, there is "high" (about 1 in 2 or 3) risk of intracranial progression.
2) There is now data that we have pretty well-tolerated, pretty low-risk drug(s) that produce responses in brain mets in about 1 out 3 properly selected patients; this is a relatively new development
Maybe don't give the "systemic" for the "systemic" disease. Give it for the brain disease. Oh and by the way it might have an effect of the systemic disease too.
I totally get, however, why some would say: don't consider it. However I do predict some will modify this viewpoint in a hopefully more data-rich future. We will see!

 

[RadOncDoc21]

This is all interesting and well and good about Stage I lung. And colon cancer etc.
But our OP said 'twas a lung adeno, diagnosed a while ago, treated with chemo in past, and had brain mets in 2017 and had SRS. Now he has new brain mets. My guess is his chance of having brain mets again in the future after SRS alone is ~90% (if he lives a year or two). There is an old saying, I'm sure you've heard it: brain mets present a high risk to a patient's health and well-being. (A new spot in the brain presents different problems than a new spot in the liver e.g.) This patient faces that 90+% recurrence risk in spades I'm afraid even if this second SRS go-'round is perfect. So here is my very limited, very particular, don't-care-about-non-CNS-systemic-disease point:
1) After SRS alone, there is "high" (about 1 in 2 or 3) risk of intracranial progression.
2) There is now data that we have pretty well-tolerated, pretty low-risk drug(s) that produce responses in brain mets in about 1 out 3 properly selected patients; this is a relatively new development
Maybe don't give the "systemic" for the "systemic" disease. Give it for the brain disease. Oh and by the way it might have an effect of the systemic disease too.
I totally get, however, why some would say: don't consider it. However I do predict some will modify this viewpoint in a hopefully more data-rich future. We will see!

I agree with your assessment and hope that we will move the data forward. I’m not against introducing new therapies but definitely value the scientific approach to lead us to the next steps.

 

[scarbrtj]

I agree with your assessment and hope that we will move the data forward. I’m not against introducing new therapies but definitely value the scientific approach to lead us to the next steps.

I sometimes fret we threw the baby out with the bathwater by putting our WBRT baby in the corner. Don't fret often; maybe just on the solstices. But WBRT did augment's SRS's intracranial control rates, and vice versa. If there's a drug that could accomplish what WBRT kinda did...

 

[Palex80]

If, in your heart of hearts, you believe that the risk of extracranial failure does not justify systemic therapy in a patient with NSCLC who has already developed brain metastases... Following SRS, I can understand why you choose to observe.

However, if you do indeed acknowledge the data showing that these patients don't live long, and more commonly die from extra-cranial failure than other causes, and you are deferring IO merely because of a whole in the RTCs... I would disagree with your reasoning.

Out of curiosity, in your experience, how have patients treated with this approach fair? Are they NED > 1-2 years?

A fair number of those patients are NED > 1 year. There are small, published surgical series.
Look at this Polish study.

Results of surgical treatment of primary lung cancer with synchronous brain metastases

The surgical treatment of non-small cell lung cancer (NSCLC) with synchronous brain matastases is more effective than other therapeutic options, but this management is still controversial.The aim of the study was to evaluate the survival of patients after ...

www.ncbi.nlm.nih.gov

30% OS at 5 years, only a fraction of the patient with "bad" pathology got systemic treatment.


Many conditions exist where the risk of systemic progression is high, yet we do not deliver adjuvant immunotherapy, because there is no data on it.
Actually, stage III NSCLC patients who receive neaoadjuvant chemotherapy and resection (without RT) do not get adjuvant IO, since PACIFIC was only for unresectable NSCLC with RCT.
These patients probably have a similar OS than the 25 stage IV patients on that Polish study, for example in the ESPATUE trial:

Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE) - PubMed

The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.

www.ncbi.nlm.nih.gov

35% at 5 years.

Just thinking that patients may benefit, does not mean they will benefit.
We need to wait on the data for the adjuvant immunotherapy trials that are currently running for NSCLC, then we can see. It is highly likely that an OS benefit will be seen. But until we have it, "adjuvant" immunotherapy (other than in the PACIFIC-setting) is not s.o.c. in my opinion.

A very nice example of how adjuvant therapies may not work the way we thought (simply because those very same drugs were highly effective for stage IV disease) is kidney cancer. Although Sunitinib and other agents are highly active in the metastatic setting, all trials on adjuvant treatment of high risk resected kidney cancer came back negative.

 

[evilbooyaa]

I am sorry, but that is incorrect.

*snip*

Well you initially quoted NCCN to support your point, so that's what I'm going with.

European guidelines may disagree, but most of us are in the US and while it's not mandatory, it is preferred to give chemotherapy perioperatively in metastatic colorectal cancer patients undergoing upfront resection. I agree that it is not MANDATORY, and if that's what you're going for, then OK, but I imagine most would give some systemic therapy.

See below:

 

[Palex80]

Well you initially quoted NCCN to support your point, so that's what I'm going with.

European guidelines may disagree, but most of us are in the US and while it's not mandatory, it is preferred to give chemotherapy perioperatively in metastatic colorectal cancer patients undergoing upfront resection. I agree that it is not MANDATORY, and if that's what you're going for, then OK, but I imagine most would give some systemic therapy.

Synchronous is not the same as metachronous. In the synchronous staging, you should give chemo.

 

[RadOncDoc21]

Synchronous is not the same as metachronous. In the synchronous staging, you should give chemo.

Why do I have such a hard time remembering these definitions? Same with a solitary vs a single lesion.

I always have to pause and remember what each means every single time.

 

[Palex80]

Why do I have such a hard time remembering these definitions? Same with a solitary vs a single lesion.

I always have to pause and remember what each means every single time.

Synchronous --> think of "synchronize" --> do it together

Metachronous --> think of "metaanalysis" --> analyze data later after all publications are there

 

[scarbrtj]

Why do I have such a hard time remembering these definitions? Same with a solitary vs a single lesion.

I always have to pause and remember what each means every single time.

The Police - Synchronicity I Lyrics | AZLyrics.com

The Police "Synchronicity I": With one breath, with one flow You will know synchronicity A sleep trance, a dream dance A shared ro...

www.azlyrics.com

 

[evilbooyaa]

Synchronous is not the same as metachronous. In the synchronous staging, you should give chemo.

Hmm fair enough. In metachronous, if 'previous chemotherapy' includes previous chemotherapy given adjuvantly, then I suppose you have a point. Thanks for the discussion.

 

[deleted1002574]

I don't get how people's feelings should trump the data. That's what gets us into trouble.

It's super expensive, it's not evidence based, and there is the potential for financial toxicity.

There is some logic to give it, but the folks that don't think there is a debate worth having .. you'd have been the same ones arguing for BMT in 1993 (I mean, if you weren't 3 years old or whatever).

It's worth it to take the time to do a study. There is logic for it's benefit. Let's go ahead and prove it.