Best dose fractionation to try to induce Abscopal in NSCLC?

[Kroll2013]

Hello dear friends,

I have a 60 yo patient, very fit that was diagnosed of a left NSCLC, that was resected and received adjuvant RT for N2 disease.
She did very well.
2 years later she developed 4 small nodules in the right Lung (controlateral) as only site for disease progression.
Biopsy revealed NCSLC , PDL-1+>90%.
She received a Immunotherapy. at the follow-up, the number of lesions increased to 7 nodules. 2 out of 7 increased in size - with one adherent to the chestwall and that may become symptomatic soon.
so we discussed to do a lung SBRT to the nodule near the chestwall to prevent from becoming symptomatic and to try to induce abscopal.

I know that per protocol, 50/5 is the best this subgroup.
My concern is that maybe a lower dose per fraction would be more adequate for abscopal.

i would appreciate your feedback.

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[RickyScott]

From what I understand the best fractionation to induce sting il2 pathway is 9-12 gy per fraction in a mouse per formenti.

 

[Palex80]

From what I understand the best fractionation to induce sting il2 pathway is 9-12 gy per fraction in a mouse per formenti.

Precisely. Do not go over 12 Gy per fraction. It's quite important to think about that in SBRT, since many of us use to prescribe to a lower isodose. 5 x 8 Gy @ 60% isodose for example means 13.33 Gy per fraction, which is beyond the "Formenti threshold".

Are these thresholds backed by clinical evidence? Nope. It's all assumptions based on experiments with a few dozen rats, but it's all we have...

I generally tend to give 3 x 10 Gy @ 100%, although I do this only in cases I do not really want to "ablate", since 3 x 10 Gy is probably too low for true ablation in most sites. Your case is one where you don't really need ablation, since you are treating only the progressive nodules. Do be aware however that the concept of not treating "all known disease" with the pure aim to induce an abscopal affect has been critisized by some people in the field. Some people are calling for treating all known sites. Abscopal effects do not have to happen on a macroscopic level. Abscopal effect does not only mean that you irradiate one lesion and another one becomes smaller. They can also happen in the microscopic level. You irradiate all known lesions and no new lesions become evident, which means the tumor-directed immune response made sure micrometastases did not become macrometastases.

Oh, and noone really knows what the ideal time schedule is. 3 fractions every day, 3 fractions every other day, 3 fraction with 1 fraction per week...

 

[Gfunk6]

From what I understand the best fractionation to induce sting il2 pathway is 9-12 gy per fraction in a mouse per formenti.

Very interesting point, I had always assumed the “hotter the better.” Food for thought.

 

[w00tz]

Very interesting point, I had always assumed the “hotter the better.” Food for thought.

Heard a talk by Jim Welsh from MDACC who does a lot of abscopal research and he thinks that lower doses may be better? I want to say like <4Gy? It was like just tickling the tumor with a bit of radiation. Something that he is looking into.

 

[seper]

What's the best level of evidence for abscopal effect thus far? At least a well-matched retrospective study? It's hard to argue for palliative SBRT with "old-school" MedOncs.

 

[RadOncMegatron]

Here is the best dose:

And what med oncs think of abscopal:

 

[scarbrtj]

From what I understand the best fractionation to induce sting il2 pathway is 9-12 gy per fraction in a mouse per formenti.

What's the best level of evidence for abscopal effect thus far? At least a well-matched retrospective study? It's hard to argue for palliative SBRT with "old-school" MedOncs.

If you ask me (no one did!) there's just as much data that radiation breeds metastasis as there is that it has abscopal, distant met effects (mouse and human data).

Radiation enhancement of metastasis: a review.
Establishment of animal model for the analysis of cancer cell metastasis during radiotherapy ("our results suggest that radiotherapy alone could promote metastasis as an undesired effect")
Mobilization of viable tumor cells into the circulation during radiation therapy.
Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot study results.
Application of a telomerase-based circulating tumor cell (CTC) assay in bladder cancer patients receiving postoperative radiation therapy: a case study.

I have no doubt an abscopal effect exists. But I also have no doubt that it is infrequent, unpredictable, and in some patients will not exist at all and in some others be "anti-abscopal"... overall a biological sfumato that will possibly be impossible to overcome.

 

[evilbooyaa]

No clinical data suggesting a difference between SBRT and standard fractionation.

Did patient have an initial response to IT? Sounds like she did not have any response, and I am very doubtful that you SBRTing one of the lesions is going to magically change that.

I favor that patients who begin IT initially have a response (or resolution of pseudoprogression). I then favor that when they progress, it is only one or two spots. I then favor treating all sites of progressive disease (oligoprogression).

I would consider it in a case when patient initially had IT response, has multiple lesions growing, and we SBRT or RT one (whatever is less toxic for the patient) to try and stimulate abscopal effect.

In the case, as presented, assuming no initial response to IT, I think patient is better served by transition to second line systemic therapy as she is not showing any response to IT and I don't think SBRT is going to rescue that.

 

[Lamount]

Hello dear friends,

I have a 60 yo patient, very fit that was diagnosed of a left NSCLC, that was resected and received adjuvant RT for N2 disease.
She did very well.
2 years later she developed 4 small nodules in the right Lung (controlateral) as only site for disease progression.
Biopsy revealed NCSLC , PDL-1+>90%.
She received a Immunotherapy. at the follow-up, the number of lesions increased to 7 nodules. 2 out of 7 increased in size - with one adherent to the chestwall and that may become symptomatic soon.
so we discussed to do a lung SBRT to the nodule near the chestwall to prevent from becoming symptomatic and to try to induce abscopal.

I know that per protocol, 50/5 is the best this subgroup.
My concern is that maybe a lower dose per fraction would be more adequate for abscopal.

i would appreciate your feedback.

There is a lot of buzz around 8 Gy x 3 (here, here, here). The beauty is, you could probably safely repeat it.

 

[RickyScott]

If you ask me (no one did!) there's just as much data that radiation breeds metastasis as there is that it has abscopal, distant met effects (mouse and human data).

Radiation enhancement of metastasis: a review.
Establishment of animal model for the analysis of cancer cell metastasis during radiotherapy ("our results suggest that radiotherapy alone could promote metastasis as an undesired effect")
Mobilization of viable tumor cells into the circulation during radiation therapy.
Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot study results.
Application of a telomerase-based circulating tumor cell (CTC) assay in bladder cancer patients receiving postoperative radiation therapy: a case study.

I have no doubt an abscopal effect exists. But I also have no doubt that it is infrequent, unpredictable, and in some patients will not exist at all and in some others be "anti-abscopal"... overall a biological sfumato that will possibly be impossible to overcome.

Fulminant/canonical abscopal effect is rare. But we are probably dealing with a spectrum here. bystander effect, or enhanced immune activity against the cancer, especially immunogenic malignancy may not be.

 

[Carotenoid]

Hello dear friends,

I have a 60 yo patient, very fit that was diagnosed of a left NSCLC, that was resected and received adjuvant RT for N2 disease.
She did very well.
2 years later she developed 4 small nodules in the right Lung (controlateral) as only site for disease progression.
Biopsy revealed NCSLC , PDL-1+>90%.
She received a Immunotherapy. at the follow-up, the number of lesions increased to 7 nodules. 2 out of 7 increased in size - with one adherent to the chestwall and that may become symptomatic soon.
so we discussed to do a lung SBRT to the nodule near the chestwall to prevent from becoming symptomatic and to try to induce abscopal.

I know that per protocol, 50/5 is the best this subgroup.
My concern is that maybe a lower dose per fraction would be more adequate for abscopal.

i would appreciate your feedback.

where did you come up with an idea that this abscopal effect is even real? geez people, gullible!

 

[evilbooyaa]

where did you come up with an idea that this abscopal effect is even real? geez people, gullible!

???

Yes it has not been well studied but to say it is definitely 'not real' seems to fly in the face of at least case reports.

 

[seper]

PEMBRO-RT has a pretty good signal. Thanks for posting that above.

 

[Carotenoid]

???

Yes it has not been well studied but to say it is definitely 'not real' seems to fly in the face of at least case reports.

Didn't say: "definitely not real". Asked: "is it even real?"

 

[Palex80]

Two trials at ASCO GU 2020 looking at abscopal effects in renal cancer by adding SBRT came out with rather ... disappointing results.

ASCO GU 2020: Adding Radiation to Immunotherapy for mRCC: Improving Systemic Control Through Local Therapy

ASCO GU 2020 metastatic renal cell carcinoma, treatment options including high dose focal radiotherapy, SBRT, synergy between radiotherapy and ICB

www.urotoday.com

 

[ramsesthenice]

Very interesting point, I had always assumed the “hotter the better.” Food for thought.

In some preclinical models that is not the case. one of the major stimuli for RT-induced INF signaling is cytosolic DS-DNA. In some models if the dose gets north of 15 Gy you induce expression of an exonuclease called TREX-1 which degrades the cytosolic DNA and abrogates STING signaling. This isn’t all cell lines but it does suggest that the hotter is better adage (to which I use to subscribe) may not be right for at least some patients.

Heard a talk by Jim Welsh from MDACC who does a lot of abscopal research and he thinks that lower doses may be better? I want to say like <4Gy? It was like just tickling the tumor with a bit of radiation. Something that he is looking into.

The data is not clear at all on this topic. many of the effects we think are necessary for the stimulation of immune responses like MHC-1antigen presentation, PD-L1 axis modulation, cytokines signaling, etc, are clearly dose responsive and are minimal at doses < 5 Gy. And actually, I think his take is a little different. I thought his idea idea to give a little bit of radiation to multiple tumors to help modulate their TME in the local environment with the thought being that the rate-limiting step for humans isn’t failed generation of Tumor-targeting Tcells but their inhibition in the TME of distant tumors. It’s an interesting thought.

 

[Palex80]

And actually, I think his take is a little different. I thought his idea idea to give a little bit of radiation to multiple tumors to help modulate their TME in the local environment with the thought being that the rate-limiting step for humans isn’t failed generation of Tumor-targeting Tcells but their inhibition in the TME of distant tumors. It’s an interesting thought.

So he proposes to treat "all disease" but only with a bit of dose?
Why won't he "push" the dose? Does a higher dose change the microenviroment in a less favorable direction than a lower dose does? Or is it simply a matter of concern ("too much dose on too many targets")?

 

[xyz01]

So he proposes to treat "all disease" but only with a bit of dose?
Why won't he "push" the dose? Does a higher dose change the microenviroment in a less favorable direction than a lower dose does? Or is it simply a matter of concern ("too much dose on too many targets")?

This paper sums up the idea quite nicely - with additional clinical data.

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy - Journal for ImmunoTherapy of Cancer

Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this...

jitc.biomedcentral.com

 

[RadOncDoc21]

I caught the abscopal!

 

[ramsesthenice]

This paper sums up the idea quite nicely - with additional clinical data.

Influence of low-dose radiation on abscopal responses in patients receiving high-dose radiation and immunotherapy - Journal for ImmunoTherapy of Cancer

Background Preclinical evidence suggests that low-dose radiation may overcome the inhibitory effects of the tumor stroma and improve a tumor’s response to immunotherapy, when combined with high-dose radiation to another tumor. The aim of this study was to evaluate tumor responses to this...

jitc.biomedcentral.com

Thank you for pulling this. I was pretty sure this was his take and I think the idea makes great sense. A major problem with most preclinical models is that they are not spontaneous tumors and they are lacking in many of the stromal constituents that act as a barrier to tumor-targeting immune cells that are present in human tumors. T-regs, TH-2 suppressor cells, and M2 macrophages are all radiosensitive so there is good reason to think you could boost the probability of achieving a measurable abscopal response.

In short, his working hypothesis is that high dose RT to one or a small number of lesions with check point inhibition does stimulate tumor-targeting Tcell clones but that we don’t see measurable abscopal responses because they can’t get in or attack the distant sites. My personal experience doing a lot of SBRT to stimulate abscopal responses largely supports this idea. I can only think of a couple times I saw true regression distantly but there have been a good number of patients who were quickly progressing on immunotherapy and almost immediately after SBRT achieved durable SD.

 

[evilbooyaa]

Thank you for pulling this. I was pretty sure this was his take and I think the idea makes great sense. A major problem with most preclinical models is that they are not spontaneous tumors and they are lacking in many of the stromal constituents that act as a barrier to tumor-targeting immune cells that are present in human tumors. T-regs, TH-2 suppressor cells, and M2 macrophages are all radiosensitive so there is good reason to think you could boost the probability of achieving a measurable abscopal response.

In short, his working hypothesis is that high dose RT to one or a small number of lesions with check point inhibition does stimulate tumor-targeting Tcell clones but that we don’t see measurable abscopal responses because they can’t get in or attack the distant sites. My personal experience doing a lot of SBRT to stimulate abscopal responses largely supports this idea. I can only think of a couple times I saw true regression distantly but there have been a good number of patients who were quickly progressing on immunotherapy and almost immediately after SBRT achieved durable SD.

Please publish your data so we can start living in a world at least defined by a retrospective series rather than by case reports. One trial that has only reported that it is 'feasible'. No other clinical data.

 

[scarbrtj]

Abscopal is rad onc’s brown note. We need abscopal to go on an episode of Mythbusters.

 

[ramsesthenice]

Please publish your data so we can start living in a world at least defined by a retrospective series rather than by case reports. One trial that has only reported that it is 'feasible'. No other clinical data.

That exact thought crossed my mind as I was writing it out this morning. I am going to give it a try but it will honestly be a challenge to do it fairly in that it will be hard to identify many of the people we did this for. You have to avoid mentioning abscopal effects in your documentation or insurers won’t cover a dime. the next best thing will be to just pull all of our SBRT cases but again, we end up billing many of these as per plan or IMRT because SBRT isn’t covered. May have to pull by fractionation schemes? It can be done, it’s just going to take some time. We all remember the times it worked but a fair analysis needs to capture the whole (or at least a good chunk) of the picture. I am also going to start keeping a better database.

 

[Carotenoid]

I caught the abscopal!

How did F let him go?

 

[w00tz]

Another anecdote, FWIW
Guy presented with stage IV NSCLC adeno with widespread mets to bone in 2015. We have him 30Gy in 10 fx in 2015 to bilateral hips. Went on to get Carbo/Taxol and Avastin x 6 cycles then Opdivo for almost 2 years, last in 1/2018. Then no further treatments, just followed with serial scans showing NED until earlier this month with mediastinal recurrence, biopsy showing adeno again.

 

[evilbooyaa]

Another anecdote, FWIW
Guy presented with stage IV NSCLC adeno with widespread mets to bone in 2015. We have him 30Gy in 10 fx in 2015 to bilateral hips. Went on to get Carbo/Taxol and Avastin x 6 cycles then Opdivo for almost 2 years, last in 1/2018. Then no further treatments, just followed with serial scans showing NED until earlier this month with mediastinal recurrence, biopsy showing adeno again.

That's a weird chemo regimen even for 5 years ago. But yes, patient recurred after stopping his systemic therapy. Took some time, but he recurred, like they almost always do (even when they're in CR forever).

But what does any of this have to do with the abscopal effect?

 

[RadOncDoc21]

That's a weird chemo regimen even for 5 years ago. But yes, patient recurred after stopping his systemic therapy. Took some time, but he recurred, like they almost always do (even when they're in CR forever).

But what does any of this have to do with the abscopal effect?

The abscopal can be used as a noun, verb or an adjective depending on the context.

 

[Palex80]

I've been using this in my talks every now and then. Feel free to use it...

I have no photoshop skills whatsoever...

 

[w00tz]

That's a weird chemo regimen even for 5 years ago. But yes, patient recurred after stopping his systemic therapy. Took some time, but he recurred, like they almost always do (even when they're in CR forever).

But what does any of this have to do with the abscopal effect?

You are right, I wouldn't necessarily call this abscopal. More under the umbrella of 'magical' happenings with cancer treatment with unexpected outcome, which is how I often feel with a prototypical observed abscopal effect.

 

[IonsAreOurFuture]

Have you ever noticed how the abscopal effect was reported in the Ipilimumab literature, but not with newer PD-L1 drugs? It's kind of a mystery. I asked Dr. Jim Allison about it (before his Nobel) at ASCO in 2017, and this was basically his answer, paraphrasing:

Jim: "PD1/PDL1 drugs act at the last step in the cellular Effector response, i.e., cytotoxic killing by otherwise exhausted, terminally differentiated CD-8 T-cells. This is a very local event."

To me this means that "AD-scopal" is a more appropriate term than "AB-scopal," and there are radiation abstracts with PD-L1 drugs describing it that way. I don't know of any major reports of PD-1 monotherapy + RT showing an abscopal effect, despite probably a million patients to date treated with PD-1 drugs. Radiation appears to synergize with PD-L1 locally, perhaps by increasing PD-L1 expression on tumor cells.

Jim: "On the other hand, CTLA-4 drugs act much earlier, during Priming, when dendritic cells are licensing CD-8 cells to kill." This activation step occurs in tumor-draining nodes. One dendritic cell can activate thousands of CD-8s, which then clonally expand and circulate through the bloodstream to find the antigen that matches their T-cell receptor.

We know that Ipilimumab + SBRT can be abscopal, as was documented in detail by Postow, et al in their classic NEJM melanoma case after ~9 Gy x3. A probable abscopal response was also reported in PRO on a patient whose tumor was growing during Ipi + Nivo for renal cell cancer, similar dose ~9.5 Gy x3.

I think Ipilimumab-containing regimens may be our best bet for now if we want to see a distant abscopal response, because Ipi can act distantly through dendritic cells. Maybe even better results will be seen with Ipi + GM-CSF (a dendritic cell growth hormone). Ipi has a reputation for toxicity, but Ipi + GMCSF is the only drug combination I've ever heard of that produces BOTH higher survival AND less toxicity than monotherapy.

It's a surprise for a drug combo of any kind, not just in oncology. GM-CSF plus 10-fraction XRT, not even SBRT, has also been shown by Dr. Encouse Golden with Dr. Sandra Demaria and Dr. Sylvia Formenti to have possible abscopal effects. I suspect this was also mediated by dendritic cells acting upstream from effector T-cells.

 

[radiation]

Have you ever noticed how the abscopal effect was reported in the Ipilimumab literature, but not with newer PD-L1 drugs? It's kind of a mystery. I asked Dr. Jim Allison about it (before his Nobel) at ASCO in 2017, and this was basically his answer, paraphrasing:

Jim: "PD1/PDL1 drugs act at the last step in the cellular Effector response, i.e., cytotoxic killing by otherwise exhausted, terminally differentiated CD-8 T-cells. This is a very local event."

To me this means that "AD-scopal" is a more appropriate term than "AB-scopal," and there are radiation abstracts with PD-L1 drugs describing it that way. I don't know of any major reports of PD-1 monotherapy + RT showing an abscopal effect, despite probably a million patients to date treated with PD-1 drugs. Radiation appears to synergize with PD-L1 locally, perhaps by increasing PD-L1 expression on tumor cells.

Jim: "On the other hand, CTLA-4 drugs act much earlier, during Priming, when dendritic cells are licensing CD-8 cells to kill." This activation step occurs in tumor-draining nodes. One dendritic cell can activate thousands of CD-8s, which then clonally expand and circulate through the bloodstream to find the antigen that matches their T-cell receptor.

We know that Ipilimumab + SBRT can be abscopal, as was documented in detail by Postow, et al in their classic NEJM melanoma case after ~9 Gy x3. A probable abscopal response was also reported in PRO on a patient whose tumor was growing during Ipi + Nivo for renal cell cancer, similar dose ~9.5 Gy x3.

I think Ipilimumab-containing regimens may be our best bet for now if we want to see a distant abscopal response, because Ipi can act distantly through dendritic cells. Maybe even better results will be seen with Ipi + GM-CSF (a dendritic cell growth hormone). Ipi has a reputation for toxicity, but Ipi + GMCSF is the only drug combination I've ever heard of that produces BOTH higher survival AND less toxicity than monotherapy.

It's a surprise for a drug combo of any kind, not just in oncology. GM-CSF plus 10-fraction XRT, not even SBRT, has also been shown by Dr. Encouse Golden with Dr. Sandra Demaria and Dr. Sylvia Formenti to have possible abscopal effects. I suspect this was also mediated by dendritic cells acting upstream from effector T-cells.

Depends on how you want to define abscopal - plenty of case reports with PD1 but the prospective today less convincing (albeit with some limited signal)

Frontiers | Abscopal Effects in Radio-Immunotherapy—Response Analysis of Metastatic Cancer Patients With Progressive Disease Under Anti-PD-1 Immune Checkpoint Inhibition

Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tu...

www.frontiersin.org

Analysis of the Abscopal Effect With Anti-PD1 Therapy in Patients With Metastatic Solid Tumors - PubMed

Abscopal effect is a rare phenomenon characterized by tumor regression of untreated metastatic lesions after a local therapy (eg, radiotherapy). We studied the probability of abscopal effect with radiotherapy associated with anti-programmed death cell 1 (PD1) therapy after progression on...

www.ncbi.nlm.nih.gov

Pembrolizumab Alone vs After Stereotactic Body Radiotherapy in Patients With Advanced NSCLC

This phase 2 randomized clinical trial assesses whether pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone enhances tumor response in patients with metastatic non–small cell lung cancer.

jamanetwork.com

ASCO GU 2020: Combination of Dual Immune Checkpoint Inhibition with Stereotactic Radiation in Metastatic Renal Cell Carcinoma (RADVAX RCC)

ASCO GU 2020 RADVAX trial, combination radiation therapy, metastatic renal cell carcinoma, combined nivolumab and ipilimumab with SBRT.

www.urotoday.com