RCT for oligomets

[thaddeus]

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Interesting trial just published showing benefit to local therapy for oligometastatic NSCLC for patients who don't progress on 1st line therapy:

https://www.ncbi.nlm.nih.gov/pubmed/27789196

The most interesting bit is that local therapy actually delayed the development of subsequent new metastatic lesions. Granted it was a post-hoc analysis, but suggests that local treatment can impact natural history in metastatic disease. Abscopal effect? Reducing continued seeding from primary?

 

[evilbooyaa]

Reduced continued seeding from primary would be my thought, but it'd be great if we could somehow prove abscopal effect (how does one prove abscopal effect anyways with concurrent systemic therapy always being given)

Iyengar had a Phase 2 trial with U Colorado folks doing something similar, but for progressive disease that failed at least 1 line of chemo. (Pubmed 25349291)

Sounds like something that UTSW/U Colorado folks do pretty frequently (Kavanagh on both papers). There's some stuff out there on oligoprogressive disease as well; for patients with more than oligometastatic disease at presentation, controlled on chemo/targeted therapies, then progress at 1 to 3 sites.

This has more patients and was actually stopped early due to too big of a difference in PFS. I have to review the whole paper but how is this not a small phase 3 RCT? They call it only a Phase II in the title.

 

[Chartreuse Wombat]

74 patients with 24 co-authors ...impressive

 

[kimplera]

74 patients with 24 co-authors ...impressive

can we add that to x+ patients over x-1 years as criteria for publication?

 

[scarbrtj]

This abscopal effect... oh how I wish we had some sense of prediction for it. The XRT-related abscopal effect has been seen in many different cancers, but my experience has been that it is capricious/highly infrequent in NSCLC. I've seen an anti-abscopal (suddenly blossoming, weirdly distributed mets) effect in NSCLC as much as I've seen the abscopal. Anecdotally, of course, I've seen more anti-abscopal responses in the peri-chemo environment; seen more abscopal in the sans chemo environment (when chemo is cytotoxic).

 

[Cancerdancer]

At time of analysis 17 of 24 in the treatment arm progressed, vs 14/25 in the observation arm.
"The overall survival data were immature"
Would've been a bit more useful to wait 6 mo for publication...

 

[mavrik13]

Because of crossover at progression, it's unlikely that there will be a significant OS difference between the arms. A tripling of PFS is significant, and more than I would have expected from this study. The era of oligometastatic disease treatment is arriving.

 

[evilbooyaa]

Because of crossover at progression, it's unlikely that there will be a significant OS difference between the arms. A tripling of PFS is significant, and more than I would have expected from this study. The era of oligometastatic disease treatment is arriving.

I think NSCLC is going to go the way of colon/rectal cancer in terms of metastatic disease and controlling primary in selected patients, especially with all these EGFR/ALK targeted therapies that can sustain people with metastatic disease for a long time. Not sure how well it will work in non-mutated patients in the long-run.

 

[seper]

For these EGFR/ALK mutated stage IV patients, it has been pretty hard to tease out real value of local therapy. Perhaps that's the disease biology that leads to decent outcomes, not XRT.

 

[evilbooyaa]

I don't necessarily think it's the inherent disease biology, although that's a hard question to answer - Do those with EGFR/ALK mutations live longer than non-mutated WITHOUT all these new therapies? That's going to be a question that is very difficult to impossible to answer.

However, I've seen a few patients with widely metastatic disease that have great response on Tarceva or Tagrisso who progress in one site, where the med-onc wants to continue with the current drug and refers the patient for spot treatment. It's difficult at times to get stereotactic technique insurance approval, however.

 

[seper]

It's especially hard to give SBRT for oligomets when people prescribing SBRT don't believe in it's value. That leads to proliferation of these ridiculous SBRT schedules like 6 Gy X 5 or 7 Gy X 3.

 

[evilbooyaa]

I mean I don't know if you need to be as aggressive as 10 x 5 or 20 x 3 for metastatic disease like you would for a primary lesion, given that the patient still does have metastatic disease, albeit oligo.

I know it's supposed to be, in theory, just like definitive treatment, but I guess i'm waffling on whether these mutated NSCLCs are truly going to be like CRC, given that these patients are essentially on maintenance systemic treatment for the rest of their life, while CRC patients routinely are on observation in-between their relapses.

 

[OTN]

I mean I don't know if you need to be as aggressive as 10 x 5 or 20 x 3 for metastatic disease like you would for a primary lesion, given that the patient still does have metastatic disease, albeit oligo.

I know it's supposed to be, in theory, just like definitive treatment, but I guess i'm waffling on whether these mutated NSCLCs are truly going to be like CRC, given that these patients are essentially on maintenance systemic treatment for the rest of their life, while CRC patients routinely are on observation in-between their relapses.

I routinely give 54 Gy in 3 fx (with heterogeneity corrections) or 50 Gy in 5 fx for SBRT for oligomets. If done correctly, toxicity is very low and local control very high. I don't see any reason to de-escalate dose, barring certain unique situations (abutting the esophagus, for example).

 

[Palex80]

We do not yet know what the optimal schedule for invoking immune effects within irradiated mets and potentially triggering abscopal effects is.
This is something which needs to ve kept in mind.

Preclinical studies show that
a) pushing the dose too hard by SRS / ablative regimes is contraproductive (possibly too much vessel damage?)
b) prolonging treatment over weeks is contraptoductive (possibly killing off lymphocytes swarming in?)

 

[seper]

are you seriously giving SBRT to invoke immune response?


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[evilbooyaa]

Papers on SBRT in oligometastatic disease discuss pushing pattern of failure from local (previous site of disease) to distant, usually with a bigger PFS.

I'm not familiar (although I haven't looked) looking at abscopal response. All these patients getting SBRT will be getting systemic treatment as well.

 

[OTN]

are you seriously giving SBRT to invoke immune response?


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I've had our medoncs give immunotx right on the heels of SBRT to try to evoke a bit of an abscopal reaction. Doesn't seem like a bad idea. (EDIT: When they were planning on giving systemic tx anyway.)

 

[radiaterMike]

are you seriously giving SBRT to invoke immune response?


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Perhaps not to invoke an immune response but to hope there is one as an ancillary benefit. I agree that attempting to do so in patients with widespread disease is investigational as is not treating all gross disease is a patient with oligomets.


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[scarbrtj]

are you seriously giving SBRT to invoke immune response?


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That's possibly-to-likely the idea.
http://www.thelancet.com/article/S1470-2045(09)70082-8/abstract
http://www.pbs.org/wgbh/nova/next/body/abscopal-response/

 

[seper]

Please don't spread this idea to patients. It's unethical.

 

[evilbooyaa]

There is a documented (mild) abscopal effect in melanoma in humans which can possibly be of (mild) clinical significance.

I'm not aware of any data in humans to support a clinical use of the abscopal effect in other diagnoses. If there is promising preclinical research, then let's get a trial going.

I don't think you can say RT + Immunotherapy means the RT is the cause for systemic control. Unless you want to run an RT alone arm, immunotherapy alone arm, and a combined arm. (or at least the IT alone and combined arm).

I think if you use SBRT for metastatic disease, your focus should be on pushing pattern of failure from local (already present sites of disease) to distant. This would mean treating all (active) lesions. I wouldn't sell SBRT to any patient with widespread metastatic disease with a discussion of the abscopal effect.

 

[Palex80]

Spreading an idea to patients can be unethical? It's an idea, not a fact.

 

[OTN]

There is a documented (mild) abscopal effect in melanoma in humans which can possibly be of (mild) clinical significance.

I'm not aware of any data in humans to support a clinical use of the abscopal effect in other diagnoses. If there is promising preclinical research, then let's get a trial going.

I don't think you can say RT + Immunotherapy means the RT is the cause for systemic control. Unless you want to run an RT alone arm, immunotherapy alone arm, and a combined arm. (or at least the IT alone and combined arm).

I think if you use SBRT for metastatic disease, your focus should be on pushing pattern of failure from local (already present sites of disease) to distant. This would mean treating all (active) lesions. I wouldn't sell SBRT to any patient with widespread metastatic disease with a discussion of the abscopal effect.

Here's a review to get started:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3845488/

Lots of exciting pre-clinical data abscopal-type response for multiple tumor cell types in murine models, and some early clinical data (prostate in this report) showing promise in humans as well. I find no ethical problem whatsoever talking with patients about potentially promising systemic benefits to the addition of SBRT for oligomets to already-prescribed immunotherapy. Potentially, naturally, being the key word. I wouldn't prescribe SBRT to evoke an immune response YET, but the data thus far looks very promising.

 

[scarbrtj]

Please don't spread this idea to patients. It's unethical.

You should immediately write a letter to the respective editors. Or attempt to shut down patients' internet access.

 

[seper]

paaahleese. give us an iota of clinical data or keep your magic potion locked up in your drawer


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