Even in era of targeted therapy, SRS doubles overall survival

[Gfunk6]

Hot off the presses from JCO: http://ascopubs.org/doi/abs/10.1200/JCO.2016.69.7144

Multi-institutional retrospective study looking at people with EGFR mutant lung cancer and brain mets. Treatment approaches were: TKI and then SRS/WBRT when symptomatic, SRS then TKI or WBRT then TKI. Respective median OS were 25, 46 and 30 months.

Obviously all caveats of retrospective study but very interesting and potentially practice changing. Authors suggest randomized trial of SRS then TKI vs TKI then SRS.


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[evilbooyaa]

Anecdotally, is anyone routinely seeing TKI instead of SRS when SRS is an option in the newly diagnosed metastatic patient? I've seen WBRT deferred in patients for TKI instead (with SRS if feasible when some of those intracranial lesions progress on MRI). I suppose in the community it's possible.

I don't like the SRS/WBRT when symptomatic arm. I'd prefer SRS/WBRT when patients show intracranial progression (either symptomatic or asymptomatic) if they are on TKI. If the trial only focuses on the patients with progression to the point of symptoms after failing TKI, they are obviously going to do worse than treating (more likely) asymptomatic lesions with SRS first. Symptomatic lesions likely means bigger, and bigger usually means harder to control, and will be reflected in median OS.

Briefly reviewing the paper:
Upfront TKI patients were more likely to have asymptomatic lesions, and were smaller (makes sense)
Upfront WBRT had poorer prognosis (makes sense)

Upfront SRS did better, but Upfront WBRT also helped patients live longer on MVA than TKI.

This line doesn't make any sense to me:
Patients treated with upfront EGFR-TKI and upfront WBRT were more likely to be stage IV at diagnosis (91% EGFR-TKI and 92% WBRT v 80% SRS; P = 0.014

Do they mean at initial diagnosis (with the remnant patients eventually progressing with intracranial disease)? What are they SRSing if patients aren't stage IV?

 

[seper]

Yeah that's pretty weak

 

[Gfunk6]

I would encourage you all to read the actual paper. I think this will address many of your questions.

The authors were certainly aware of the inherent bias between patient selection for initial therapy. However they stratified all patients in the three treatment arms by prognostic category so that "apples to apples" were being compared.

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[Mandelin Rain]

I was told that WBRT was evil in NSCLC and should never be used again (unless if you're a greedy, system sucking low-life). So... I don't believe the curves above.

Anyway, I'd be pretty mad at my med onc if he sat on treatable intracranial disease to give a TKI. Luckily, I've never seen it happen.

 

[RadOncDoc21]

You guys are way smarter than I am... I read everybody's post on here and still have no idea what the conclusion is or even what the argument is about.

 

[evilbooyaa]

I think all this paper shows that despite the papers showing some evidence of TKI in crossing the blood brain barrier, med-onc should stop dicking around and refer their brain met patients to Rad Onc for a better treatment (either SRS or WBRT). Lol @Mandelin Rain I don't think QUARTZ is going to be taken too seriously by most rad oncs in the US.

Some med-oncs already will put a patient through infinite Xgeva instead of considering palliative RT for a few bony mets, so all this is saying is that TKI isn't going to eliminate business from Rad-oncs treating intracranial disease in EGFR NSCLC.

I'm truly surprised that the number of patients in a retrospective review that WERE treating their brain mets with TKI alone is that high. If I was in the community and that was going on without even a consultation with a Rad Onc, I'd be pretty upset. If I see the patient and they refuse therapy and want to try TKI, fine, I can live with that. But not referring (especially for SRS) because they have an EGFR mutation and going with TKI alone?

 

[OliveTree]

You guys are way smarter than I am... I read everybody's post on here and still have no idea what the conclusion is or even what the argument is about.

 

[OliveTree]

I think all this paper shows that despite the papers showing some evidence of TKI in crossing the blood brain barrier, med-onc should stop dicking around and refer their brain met patients to Rad Onc for a better treatment (either SRS or WBRT). Lol @Mandelin Rain I don't think QUARTZ is going to be taken too seriously by most rad oncs in the US.

Some med-oncs already will put a patient through infinite Xgeva instead of considering palliative RT for a few bony mets, so all this is saying is that TKI isn't going to eliminate business from Rad-oncs treating intracranial disease in EGFR NSCLC.

I'm truly surprised that the number of patients in a retrospective review that WERE treating their brain mets with TKI alone is that high. If I was in the community and that was going on without even a consultation with a Rad Onc, I'd be pretty upset. If I see the patient and they refuse therapy and want to try TKI, fine, I can live with that. But not referring (especially for SRS) because they have an EGFR mutation and going with TKI alone?

QUARTZ interestingly showed an OS benefit to whole brain radiotherapy in subset of young patients. Kind of encouraging for whole brain for the properly selected patient.

 

[evilbooyaa]

QUARTZ interestingly showed an OS benefit to whole brain radiotherapy in subset of young patients. Kind of encouraging for whole brain for the properly selected patient.

That's the issue, though. You can't say that a paper is crap from one side of your mouth, and how you're not going to let it affect your practice (like not offering WBRT for anyone not eligible for SRS), then talk about a very interesting conclusion they came to in a subset of that population.

WBRT is here to stay in some fashion, IMO. SRS will get more prevalent and the number of lesions that can be SRS'd with single isocenter will continue to increase. However, the urge to 'do something' for patients who aren't actively on death's door is significant. WBRT is getting deferred by patients more and more often, but when SRS isn't an option, I've very rarely seen a rad onc recommend against it (only in the young patient with EGFR NSCLC with 30+ tiny mets, asymptomatic, so recommended TKI therapy first).

 

[evilbooyaa]

How do you get this conclusion based on the cohorts?

Also, difference in survival could easily be based on sicker patients getting WBRT.

Plus, this is only for patients with intracranial mets, which TKI's suck at treating.

I can guarantee you that SRS and WBRT are quite awful at treating extracranial metastases, FWIW.

Given that recent papers have shown activity of certain EGFR inhibitors within the brain (usually Tarceva or Tagrisso are what I see) there has been some discussion about reserving radiation for salvage of previously TKI-controlled intracranial disease.

So it is relevant that there was a survival advantage (looking at similar GPA for stratification as GFunk pointed out) to doing SRS first.

 

[OliveTree]

That's the issue, though. You can't say that a paper is crap from one side of your mouth, and how you're not going to let it affect your practice (like not offering WBRT for anyone not eligible for SRS), then talk about a very interesting conclusion they came to in a subset of that population.

WBRT is here to stay in some fashion, IMO. SRS will get more prevalent and the number of lesions that can be SRS'd with single isocenter will continue to increase. However, the urge to 'do something' for patients who aren't actively on death's door is significant. WBRT is getting deferred by patients more and more often, but when SRS isn't an option, I've very rarely seen a rad onc recommend against it (only in the young patient with EGFR NSCLC with 30+ tiny mets, asymptomatic, so recommended TKI therapy first).

I agree. Calling the paper crap is not productive. Calling the overall conclusions by the authors oversimplified, by pointing to the raw data within the study, is a better approach IMO.

 

[medgator]

Given that recent papers have shown activity of certain EGFR inhibitors within the brain (usually Tarceva or Tagrisso are what I see) there has been some discussion about reserving radiation for salvage of previously TKI-controlled intracranial disease.
.

The problem is we all know that tki therapy never cures disease, and eventually the cancer becomes resistant to it.

I think the paradigm should be similar to small cell where we can defer wbrt for a little while to get the extracranial disease under control if it's a bad burden before doing srs and/or wbrt depending on the situation. Etoposide has activity in the brain too but I would never pretend that it's something that allows me to defer treating brain mets indefinitely with potentially ablative local therapy.

 

[evilbooyaa]

The problem is we all know that tki therapy never cures disease, and eventually the cancer becomes resistant to it.

I think the paradigm should be similar to small cell where we can defer wbrt for a little while to get the extracranial disease under control if it's a bad burden before doing srs and/or wbrt depending on the situation. Etoposide has activity in the brain too but I would never pretend that it's something that allows me to defer treating brain mets indefinitely with potentially ablative local therapy.

I think the issue that's hard to get by is that if you do that (TKI first to control extracranial disease), and the disease in the brain disappears, or shrinks, and is stable, it's a hard sell to patients and med-oncs to say that we need to treat those lesions with radiation (especially with whole brain).