SRS Brain for Melanoma on Nivolumab and Ipilimumab?

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Mandelin Rain

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Anyone doing this? Lit search shows promise of SRS with immunotherapy but I don't see a whole lot of safety in humans type data.
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There are a number of recent publications about brain radiosurgery and immune therapy:

https://www.ncbi.nlm.nih.gov/pubmed/26544782

I'm not sure if anyone knows the best way to go about this with regards to stopping or continuing.

I haven't treated anyone on dual nivolumab and ipilumumab with single or 5 fraction brain SRS, but I have treated some patients on nivolumab as monotherapy. Generally what we've done is keep them on it and not stop it during radiosurgery, especially if they have systemic disease that is responding well to it....

With that said, my experience has been similar to that in the recent literature where I have been seeing more FLAIR change or initial "swelling" of the target/tumor more than I usually see. I haven't had any major radionecrosis, but just a slight increase in swelling/symptoms, but typically has not resulted in me needing to start steroids.
 
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IMHO, NO NO for Yervoy as it appears to cause intracranial hemorrhage with WBRT
 
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seper said:
IMHO, NO NO for Yervoy as it appears to cause intracranial hemorrhage with WBRT
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I edited my post above - I meant to say I've treated some patients on Opdivo/Nivolumab with SRS without stopping. Don't think I've had any on ipilumimab.

Some of the publications (and my experience) suggests that even stopping the immune therapy and/or starting immune therapy after brain SRS increases necrosis risk.
 
We see a lot of melanoma here and I have treated a number of patients. Had a case of radionecrosis requiring steroids, but nothing out of the ordinary. Moffitt had a recent paper showing 80% one year local control in fractionated radiosurgery on checkpoint inhibitors for a large number of patients.
I went to the NCI conference on immunotherapy and radiation in April. The consensus from the preclinical data was that if you are looking for the abscopal effect, the immunotherapy should be delivered first based on work by Levy's lab at Stanford.

Both antibodies circulate in the bloodstream for 2 -3 weeks - so if the patient needs stereo, you are going to be forced into it.
 
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I think it's relatively safe to do it. People have been talking about ibcreased risks of bleeding im melanoma mets being treated by SRS and immunotherapy, but:
a) melanoma brain mets tend to bleed all the time with or without treatment
b) patients with metastatic melanoma used to have a very poor survival in the past. Maybe we didn't see that much bleeding cause most patients died from tumor progression before they got to the point of bleeding or developing necrosis in the first place?

We generally allow ipilimumab parallel to SRS. In cases of nivolumab or pembrolizumab we ask the med oncs to "skip" one infusion and deliver SRS "in between", so that we have a time frame of 2-3 weeks before and after SRS without an infusion.
That's zero evidence based. :)
 
nkmiami said:
Moffitt had a recent paper showing 80% one year local control in fractionated radiosurgery on checkpoint inhibitors for a large number of patients.
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https://academic.oup.com/annonc/art...linical-outcomes-of-melanoma-brain-metastases

This paper? Only 5 lesions (7%) were treated concurrently.

When I was at Moffitt, we used Palex's approach. This is still my approach. I generally try to avoid concurrent SRS and immunotherapy agents, but if push comes to shove I have done it.

Palex: I wouldn't say zero evidence. Many of the trials also do this--radiation "washout" periods and all that.
 
Yeah, if anyone has a good series of Yervoy+SRS at your center, you should publish ASAP
 
How can you wait several weeks in melanoma patients, especially if they have symptoms and are on a checkpoint inhibitor. The immunological effects (hopefully) persist after the antibody exits circulation, so what is accomplished by the "washout period?" These drugs (with the exception of the pdl1 receptor blocker) dont target/interact or bind to the the tumor as far as I know. They bind to and "release the brakes" " on lymphocytes?
 
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nkmiami said:
How can you wait several weeks in melanoma patients, especially if they have symptoms and are on a checkpoint inhibitor. The immunological effects (hopefully) persist after the antibody exits circulation, so what is accomplished by the "washout period?" These drugs (with the exception of the pdl1 receptor blocker) dont target/interact or bind to the the tumor as far as I know. They bind to and "release the brakes" " on lymphocytes?
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There are alot of unknowns here. I think one point is that high-dose radiation therapy, like used in SRS, induces a massive inflammation and cytokine release due to the massive cell kill in the tumor but as well due to damage to vessels, etc.
Stimulating the immune system at the same time with one of the new drugs may cause not expected events.
Surely the lymphocytes stay activated after the infusion, but theres probably still a difference if you give the medication the same time as the SRS.
 
  1. There are unknowns, but a delay in xrt carries known risks of bleeds and neurological symptoms and excess steroids , and certainly wouldnt delay stereo by 3 weeks.
  2. I am not sure if there is immediate massive cell kill or not- tumors take time to shrink, as most cell kill is thought to be due to mitotic death and requires multiple divisions. Maybe delaying the stereo results in the drug being delivered when mitotic death occurs. We just dont know, and I am not sure it is helpful to think of them like chemotherapy.
 
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I'm not talking large, symptomatic mets. Something like two 1 cm mets. No edema. No symptoms. The med onc thinks they'll disappear with the combo treatment alone. I'm more dubious, but don't want to treat concurrently just to do it for the uncertainties/lack of data above. I'm planning 6 week MR follow up.

Would have been nice had he held off on initiation of therapy for a week so we could treat him first, rather than start on the day the referral was ordered. But alas, these are the things we deal with.
 
nkmiami said:
1. There are unknowns, but a delay in xrt carries known risks of bleeds and neurological symptoms and excess steroids , and certainly wouldnt delay stereo by 3 weeks.
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Well our linacs are pretty busy anyways, so usually a patient needs to wait 2 weeks to get treatment anyway. :) But, yes, I understand your concern. If you talk with your oncologist however, you can solve this problem most of the times.

2. I am not sure if there is immediate massive cell kill or not- tumors take time to shrink, as most cell kill is thought to be due to mitotic death and requires multiple divisions. Maybe delaying the stereo results in the drug being delivered when mitotic death occurs. We just dont know, and I am not sure it is helpful to think of them like chemotherapy.
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Fractionated RT leads to mitotic death. SRS with single doses of 20-25 Gy leads to major cell killing during treatment and in the immediate hours/days following it. It's a whole different effect, which is why many of us prescribe steroids for example, when giving SRS.
It's the same for most high-dose-per-fraction treatments. I have seen patients with big NSCLC primaries or big liver mets, who got 10-20 Gy per fraction SBRT and had shivers a couple of hours after each treatment. This is not something you see, when you hit a stage IIIB NSCLC with 2 Gy fractions. It's a different mechanism, probably a massive release of cytokines due to the immediate damage produced by treatment both to tumor and to the surrounding tissue.
 
getting kind of esoteric here- I agree large treatments cause cytokine release. Zvi Fuks had a paper in Nature 7 or 8 years ago that indicated apoptotic/immediate tumor death and death of tumor vasculature/stroma from stereotactic doses. No one else could ever replicate (hmm) his results and as far as I know stereotactic treatment most likely just causes mitotic death according to the radiobiologists I have spoken with, but maybe someone else with more knowledge can weigh in.
 
nkmiami said:
getting kind of esoteric here- I agree large treatments cause cytokine release. Zvi Fuks had a paper in Nature 7 or 8 years ago that indicated apoptotic/immediate tumor death and death of tumor vasculature/stroma from stereotactic doses. No one else could ever replicate (hmm) his results and as far as I know stereotactic treatment most likely just causes mitotic death according to the radiobiologists I have spoken with, but maybe someone else with more knowledge can weigh in.
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This is common sense.
It's why you are dead within hours of getting 20+ Gy delivered to your entire CNS and not within days. It happened to dozens of firefighters putting out the fire in Chernobyl. They were standing on the ground next to the radioactive graphite blown out from the roof of the building. Within hours they started vomitting and then died. This has noting to do with mitotic death. They died from brain edema. Brain edema caused by dying cells. And most cells in the brain are not mitotic at all.
This is what you do with SRS too: Chernobyl in a smaller volume = PTV.
 
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Fake news, mate.

https://en.wikipedia.org/wiki/Death...r#Deaths_due_to_trauma_and_radiation_sickness


Palex80 said:
This is common sense.
It's why you are dead within hours of getting 20+ Gy delivered to your entire CNS and not within days. It happened to dozens of firefighters putting out the fire in Chernobyl. They were standing on the ground next to the radioactive graphite blown out from the roof of the building. Within hours they started vomitting and then died. This has noting to do with mitotic death. They died from brain edema. Brain edema caused by dying cells. And most cells in the brain are not mitotic at all.
This is what you do with SRS too: Chernobyl in a smaller volume = PTV.
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I am no expert on this, but I was under impression that huge doses of radiation cause massive cytokine release without cell death in these cases - was one of the first chapters in Hall.
 
seper said:
Fake news, mate.

https://en.wikipedia.org/wiki/Death...r#Deaths_due_to_trauma_and_radiation_sickness
Click to expand...

Sorry, I was under the impression that they died earlier, most seemed to survive 1-2 weeks before dying.

Yet, the graphite story seems to be true:
https://timster1973.wordpress.com/2012/10/13/the-firefighters-of-chernobyl/

And they probably received sonething like 20 Gy:
http://www.world-nuclear.org/inform...rity/safety-of-plants/chernobyl-accident.aspx

The casualties included firefighters who attended the initial fires on the roof of the turbine building. All these were put out in a few hours, but radiation doses on the first day were estimated to range up to 20,000 millisieverts (mSv), causing 28 deaths – six of which were firemen – by the end of July 1986.


Are you questionning the theory of non-mitotic damage and subsequent death due to doses >20 Gy delivered to the entire CNS?
 
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I am really not on solid footing here. Certainly everyone dies and massive cytokines are released- I would have to check with a radiobiologist if there is non mitotic death. This was from Hall's group.

Anecdotally, the few times I have seen a MRI within a week or 2 of radiosurgery (patient admitted with complaints of HA etc) there was no substantial change in tumor size or evidence of tumor necrosis, which I would think would be the case if there was massive apoptosis in the radiated PTV. In the early days of lung SBRT, a colleague of mine got pet scans on 2 patients the day after lung sbrt (20Gy x 3). There was no change.



Editorial

Dose Escalation, Not “New Biology,” Can Account for the Efficacy of Stereotactic Body Radiation Therapy With Non-Small Cell Lung Cancer


http://dx.doi.org/10.1016/j.ijrobp.2012.11.003
 
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There is certainly non-mitotic damage delivered directly to cells that do not grow.
This is how irradiation of AVMs works. AVMs are non-mitotic. When you irradiate them however you enduce structural damage to the cells on the vessels leading to their obliteration (through fibrosis?) over time.
 
That may be true, but I also imagine that vessels have pericytes in the walls that do reproduce and the loss of the pericytes could contribute to fibrosis. In the case of nerves, glial cells do reproduce.

For trigeminal neuralgia I have no idea how XRT works, are you basically targeting an axon with no DNA present? but even then the effect is often delayed
 
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nkmiami said:
That may be true, but I also imagine that vessels have pericytes in the walls that do reproduce and the loss of the pericytes could contribute to fibrosis. In the case of nerves, glial cells do reproduce.

For trigeminal neuralgia I have no idea how XRT works, are you basically targeting an axon with no DNA present? but even then the effect is often delayed
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Radiation therapy does not only cause mitotic damage to cells. It can also destroy mitochondria, damage the endoplasmatic reticulum and punch holes into the cell membrane. This effects are known. They are less prominent in photon irradiation but make up for a lot of the damage produced by heavy ion treatment. On the other hand if you increase the dose dramatically (20 Gy of SRS are still the 10-fold-dose of a normal 2 Gy fraction) one can speculate that effects like these gain in importance.
This is also probably why SRS works so well with local control rates of 90%, although it's a single shot treatment. Being a single shot treatment also means that thousands of cells will be hit in a radiation-resistance cell cycle phase (by chance) and/or a a hypoxic state. Reoxygenation and Redistribution don't work in SRS. Yet local failures are seldom. And this is probably because damage is being delivered by means which are not bound to the Rs.
 
Palex80 said:
Radiation therapy does not only cause mitotic damage to cells. It can also destroy mitochondria, damage the endoplasmatic reticulum and punch holes into the cell membrane. This effects are known. They are less prominent in photon irradiation but make up for a lot of the damage produced by heavy ion treatment. On the other hand if you increase the dose dramatically (20 Gy of SRS are still the 10-fold-dose of a normal 2 Gy fraction) one can speculate that effects like these gain in importance.
This is also probably why SRS works so well with local control rates of 90%, although it's a single shot treatment. Being a single shot treatment also means that thousands of cells will be hit in a radiation-resistance cell cycle phase (by chance) and/or a a hypoxic state. Reoxygenation and Redistribution don't work in SRS. Yet local failures are seldom. And this is probably because damage is being delivered by means which are not bound to the Rs.
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All that is true, and probably there is some immune mediated death as well as. XRT causes increased expression of MHCII/antigen expression etc (tumors in nude mice require double the dose of xrt for control).
I guess I have been underwhelmed by immediate radiological changes after huge doses when we used to give 20 Gy x 3 for lung. Initially, my department did a lot of post treatment imaging in these patients and really didnt see significant radiological changes for at least 4-6 months.

also regarding fractionation,

Clin Cancer Res. 2009 Sep 1;15(17):5379-88. doi: 10.1158/1078-0432.CCR-09-0265. Epub 2009 Aug 25.
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody.
Dewan MZ1, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S.
Author information

Abstract
PURPOSE:
This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody.

EXPERIMENTAL DESIGN:
TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.

RESULTS:
In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the inhibition of the secondary tumor.

CONCLUSIONS:
Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
 
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nkmiami said:
I guess I have been underwhelmed by immediate radiological changes after huge doses when we used to give 20 Gy x 3 for lung. Initially, my department did a lot of post treatment imaging in these patients and really didnt see significant radiological changes for at least 4-6 months.
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Really? I've seen CBCT changes within week 2 in patients getting SBRT or hypo-fractionated/accelerated lung Tx
 
medgator said:
Really? I've seen CBCT changes within week 2 in patients getting SBRT or hypo-fractionated/accelerated lung Tx
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Me too.
And I've seen shivers within hours of SBRT for big tumors. Probably dying cells and cytokine release.
 
larger tumors do start to shrink - I am referring to the typical 1-2 cm adeno that we give stereotactic to, and I have almost never seen early normal tissue changes, which would be expected with necrosis. I have also had patients who had cytokine release type symptoms- mostly excessive fatigue.
 
medgator said:
Really? I've seen CBCT changes within week 2 in patients getting SBRT or hypo-fractionated/accelerated lung Tx
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Usually we see the lesion get bigger in SBRT (say, 5fx lung) if it was small to begin with on daily CBCTs. Rarely see a lesion actually shrink during conebeams.
 
evilbooyaa said:
Usually we see the lesion get bigger in SBRT (say, 5fx lung) if it was small to begin with on daily CBCTs. Rarely see a lesion actually shrink during conebeams.
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same here.
Anyway, read the 2 articles posted earlier in the thread from Yale and MSKCC and both suggest that patients did better with concurrent use of checkpoint inhibitors and SRS, although there was more radionecrosis/pseudoprogresion of the lesions. Maybe, we should be making an effort to combine them?

(Yale) "RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). "


- (MSKCC) "Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly due to enhanced immunomodulatory effect."
 
nkmiami said:
same here.
Anyway, read the 2 articles posted earlier in the thread from Yale and MSKCC and both suggest that patients did better with concurrent use of checkpoint inhibitors and SRS, although there was more radionecrosis/pseudoprogresion of the lesions. Maybe, we should be making an effort to combine them?

(Yale) "RN/TRIC rates were 37.5% (12 of 32) in patients who received IT alone, 16.9% (14 of 83) in those who received CT only, and 25.0% (5 of 20) in those who received TT only. Median overall survival was significantly longer in patients who developed RN/TRIC (23.7 vs 9.9 months, respectively). "


- (MSKCC) "Overall, the combination of Ipi and SRS appears to be well tolerated. Concurrent delivery of Ipi and SRS is associated with favorable locoregional control and possibly longer survival. It may also cause a temporary increase in tumor size, possibly due to enhanced immunomodulatory effect."
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I think that's survivor bias, IMO, in saying that doing things that can lead to TRICs (Treatment-related imaging changes) may lead to better OS.

Patient's who live longer are more likely to develop radionecrosis than those who die, so I don't think the Yale paper is supportive of IT + SRS.

What's the MSKCC paper? Can't find it in the various links posted above.
 
evilbooyaa said:
I think that's survivor bias, IMO, in saying that doing things that can lead to TRICs (Treatment-related imaging changes) may lead to better OS.

Patient's who live longer are more likely to develop radionecrosis than those who die, so I don't think the Yale paper is supportive of IT + SRS.

What's the MSKCC paper? Can't find it in the various links posted above.
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good point- i am being a bit of a troll
here is the MSKCC from above
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4955924/
 
I don't think anyone died of CNS syndrome among Chenrobyl responders. Timelines in wikipedia article clearly indicate GI and BM syndromes. You need 50 Gy to entire CNS to cause immediate death.

Palex80 said:
Sorry, I was under the impression that they died earlier, most seemed to survive 1-2 weeks before dying.

Yet, the graphite story seems to be true:
https://timster1973.wordpress.com/2012/10/13/the-firefighters-of-chernobyl/

And they probably received sonething like 20 Gy:
http://www.world-nuclear.org/inform...rity/safety-of-plants/chernobyl-accident.aspx

The casualties included firefighters who attended the initial fires on the roof of the turbine building. All these were put out in a few hours, but radiation doses on the first day were estimated to range up to 20,000 millisieverts (mSv), causing 28 deaths – six of which were firemen – by the end of July 1986.


Are you questionning the theory of non-mitotic damage and subsequent death due to doses >20 Gy delivered to the entire CNS?
Click to expand...
 
seper said:
I don't think anyone died of CNS syndrome among Chenrobyl responders. Timelines in wikipedia article clearly indicate GI and BM syndromes. You need 50 Gy to entire CNS to cause immediate death.
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Source for that?

I was under the impression that CNS-death can be achieved with doses >10 Gy to the entire CNS within a few days. I recall there was a patient series for palliative WBRT where high-dose single shot irradiation was given and several people died due to the edema.
"Immediate death" within hours indeed needs greater doses, but you don't need 50 Gy for that. I think you can achieve that with 30 Gy or so too.
 
Palex80 said:
Single-fraction WBRT has been tried before and deemed unsafe
https://www.ncbi.nlm.nih.gov/pubmed/5424525

1 x 10 Gy WBRT for brain mets. 3/54 patients dead "within hours".
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Dude did you actually read that paper? It was from 1970 and its actually a pretty interesting look into the time. CT scans were obtained, but no MRI's. At that time patients presented with massive symptomatic brain mets and newly diagnosed brain mets were a true emergency requiring same day treatment. Look at the paper, 18 of 54 were hemiparetic, and 3 were comatose, others had cranial neuropathies all prior to treatment. The 3 that died were obtunded and they really only attribute 1 death due to radiation induced swelling, most likely patient had pre-existing increased ICP, and XRT caused herniation, or alternatively could have just been hemorrhage during treatment unrelated to radiation. 10Gx1 is not that insane.. there are modern series looking at 500cGy x4 whole brain, or some studies in the 90's which looked at 6Gy x 2. I'm not advocating single fraction whole brain radiation, but just saying I had a hospitalized patient die during 300cGy x10 due to hemorrhage, had nothing to do with radiation regimen.
 
Yeah, Palex I'm not sure what are you arguing here, radiation CNS syndrome is like in the first chapter of all RadBio/RadOnc books.
 
Phantom1 said:
Dude did you actually read that paper? It was from 1970 and its actually a pretty interesting look into the time. CT scans were obtained, but no MRI's. At that time patients presented with massive symptomatic brain mets and newly diagnosed brain mets were a true emergency requiring same day treatment. Look at the paper, 18 of 54 were hemiparetic, and 3 were comatose, others had cranial neuropathies all prior to treatment. The 3 that died were obtunded and they really only attribute 1 death due to radiation induced swelling, most likely patient had pre-existing increased ICP, and XRT caused herniation, or alternatively could have just been hemorrhage during treatment unrelated to radiation. 10Gx1 is not that insane.. there are modern series looking at 500cGy x4 whole brain, or some studies in the 90's which looked at 6Gy x 2. I'm not advocating single fraction whole brain radiation, but just saying I had a hospitalized patient die during 300cGy x10 due to hemorrhage, had nothing to do with radiation regimen.
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I've had patients die during 10 x 3 Gy too.
However both the autors and other articles citing this paper deemed that the 1 x 10 Gy approach is unsafe.
"Dying within hours" of 1 x 10 Gy seems to be a bit concerning. But hey, if you want to try it out, go ahead.
 
seper said:
Yeah, Palex I'm not sure what are you arguing here, radiation CNS syndrome is like in the first chapter of all RadBio/RadOnc books.
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What I am arguing about:

1. SRS does not cause only mitotic death. It causes immediate cellular death due to damage to beyond the DNA. It destroys mitochondria, the cell membrane, shuts down vascularization of the tumor, etc. This results in a massive cytokine release, which in turn is what you may see if you do a CT scan a couple of days after SRS = edema around the treated site and the reason why some of us prescribe steroids as a prophylaxis when delivering SRS.
2. SRS produces more or less the same effect of an incidental irradiation to the entire CNS as seen in accidents, yet in a local level. That's why you don't die. But the biology behind it is basically the same.
3. Doses around 30 Gy delivered as single treatment to the entire CNS (and probably doses even lower than that) are lethal. This effect has nothing to do with mitotic death.

:)
 
I find this really interesting and have never gotten a good answer. There is no doubt that massive cytokines are released, but what is in doubt is whether this is from immediate cell death. I just dont think we have an answer if there is anything more than mitotic death.

the 5 Rs Involved?


http://dx.doi.org/10.1016/j.ijrobp.2013.07.022
Get rights and content

Referred to by
Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because of technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.
 
Palex80 said:
What I am arguing about:

1. SRS does not cause only mitotic death. It causes immediate cellular death due to damage to beyond the DNA. It destroys mitochondria, the cell membrane, shuts down vascularization of the tumor, etc. This results in a massive cytokine release, which in turn is what you may see if you do a CT scan a couple of days after SRS = edema around the treated site and the reason why some of us prescribe steroids as a prophylaxis when delivering SRS.
2. SRS produces more or less the same effect of an incidental irradiation to the entire CNS as seen in accidents, yet in a local level. That's why you don't die. But the biology behind it is basically the same.
3. Doses around 30 Gy delivered as single treatment to the entire CNS (and probably doses even lower than that) are lethal. This effect has nothing to do with mitotic death.

:)
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This is all true! :happy:
 
What type of immediate cell death from DNA damage is possible other than apoptosis?
 
nkmiami said:
What type of immediate cell death from DNA damage is possible other than apoptosis?
Click to expand...

Not saying this is what happens but direct membrane rupture could be one cause. Also devascularization from vascular endothelial apoptosis as opposed tumor apoptosis (MSKCC science paper advocates this and is mentioned above)


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