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Sirtuin activation, the pressunrd mechanism of hormesis is highly immunomodulatory.I don't think it has to do with hormesis. It's immunomodulatory.
Sirtuin activation, the pressunrd mechanism of hormesis is highly immunomodulatory.I don't think it has to do with hormesis. It's immunomodulatory.
Exactly who has time for phase 1-2 RT study when hospitals are overrun. Safety won't be able to be elucidated beyond did they die immediately after from RT.
Complete waste of resources. This is honestly what happens when academic volume hits rock bottom. Too much time on their hands
We already have adequate safety/toxicity data on whole lung RT, at doses well above 1Gy, so it should be phase 2 or randomized phase 2. Only reason for phase I/II may be to study dose de-escalation from a starting dose of 1Gy and reduce to perhaps 0.3Gy, which is what I think Palex80 was implying, but is it really worth it at such low starting dose??
And who has time for phase 1-2 COVID studies? Well, let see, every vaccine studies right now are phase I and most intervention trials are phase 2, which include non-drug trials such as device-related testing. Lets not be so insecure about our potential contributions to this crisis... And please lets try to keep our attitude in check, especially if at your point in your career you think we don't have safety data on whole lung irradiation, at 1 Gy....
There are logistical issues currently that no cancer trial has ever had
specifically the shortage of health care workers. Are you going to move a vented patient right now? That requires chaperone from ICU (nurse or MD), which are already short staffed at major hospitals. We have senior diagnostic radiology in ICU at this point
For non vented patient Are you going to risk Codes happening in rad Onc dept? again that will divert frontline medical staff
for drug phase 1 trials you don’t have That issue
Exactly who has time for phase 1-2 RT study when hospitals are overrun. Safety won't be able to be elucidated beyond did they die immediately after from RT.
Complete waste of resources. This is honestly what happens when academic volume hits rock bottom. Too much time on their hands
The data are there, but they are not there for COVID patients with pneumonia.We already have adequate safety/toxicity data on whole lung RT, at doses well above 1Gy, so it should be phase 2 or randomized phase 2.
Or you could go the other way around. Start with lower doses and increase, since we do not really know what kind of dose we would need... Needless to say those data from the 20s and 30s have dosimetry of the 20s and 30s. I have no idea what kind of radiation dose was really delivered back then...Only reason for phase I/II may be to study dose de-escalation from a starting dose of 1Gy and reduce to perhaps 0.3Gy, which is what I think Palex80 was implying, but is it really worth it at such low starting dose??
Good dovetailing of Dickens and respiratory issues...To paraphrase Charles Dickens, from his 1859 hallowed epic, “ A Tale of Two Cities”, “These are the best of times (the ecosystems are healing), these are the worst of times (thousands are dying), this is the age of wisdom (we have deciphered the genome of our enemy within days), this is the age of foolishness (several organizations are actively violating social distancing principles), this is the epoch of belief (in a trial like we propose here), this is epoch of incredulity (incredulous that radiation, which in higher doses can damage the lungs could have a chance at halting and reversing lung damage when used at ultra-low doses), this is the season of light (read…radiation, electromagnetic cousins), this is the season of darkness (80% mortality for long-term ventilated COVID-19 pneumonia patients), this is the season of hope (hoping that intelligent historic experiences can guide an expeditious clinical trial in the time of a pandemic), this is the winter of despair (because almost nothing else seems to be working for our ventilated patients). As Dickens went on to say, “in short, the period was so far like the present period.” We agree, we need radical thinking; now is not the time for the perfect to be the enemy of the good; the need of the hour is to mount a practical, ethical, and as safe as possible trial, expeditiously, in a collaborative, nation-wide effort."
I would love to send a time machine to retrieve the young Weichselbaum, who did not get fazed by all the old cranky oncologists in the heyday that ridiculed his radical oligometastatic paradigm, and bring him face to face this old cranky Weichselbaum. Oh the irony......
I actually agree with Weichselbaum here. We are digging up data from the 40s (30s?) to actually treat ventilated patients with 100 cGy? I'd rather turf war the derms and use XRT for acne. Perhaps a SRS FFF with Frame (can let derms put on if they are salty) and fused with post-contrast 7T MRI seq. (gotta use the best) to ensure we use everything.
Calling it a "phase II trial" does not make it more legitimate.
After this is all over, then yes, why not do some more up to date pre-clinical studies and phase 1 analyses on other viral patients and then we can talk about actually treating critical patients on vents during a global pandemic with resource limitations.
Now on the other hand people dug up data from the 30's to use in the 40's. And then dug up data in the 40's to use in the 1950's... etc... and in the 1980's and 1990's ~90% of that thinking was still carried through. And most of that "data" is still in use today! If we didn't (constantly) dig up old (non-randomized data) data from a ~century ago we wouldn't have a specialty. (There is no randomized data that the main tool now in use in modern rad onc, the linac, is clinically superior/inferior to what it replaced e.g. The ubiquitous 6MV beam was meant to be cobalt-y, and so on, and so forth.)I actually agree with Weichselbaum here. We are digging up data from the 40s (30s?) to actually treat ventilated patients with 100 cGy? I'd rather turf war the derms and use XRT for acne. Perhaps a SRS FFF with Frame (can let derms put on if they are salty) and fused with post-contrast 7T MRI seq. (gotta use the best) to ensure we use everything.
Calling it a "phase II trial" does not make it more legitimate.
After this is all over, then yes, why not do some more up to date pre-clinical studies and phase 1 analyses on other viral patients and then we can talk about actually treating critical patients on vents during a global pandemic with resource limitations.
i agree with your sentiment. Interesting question but just can’t ever see it getting to phase 3 in this disease in which medical therapy will move rapidly. Maybe get a signal here to apply radiation in other areas.I disagree. It will likely be a bust, but there are legit pre-clinical and clinical data supporting low dose RT in the treatment of severe viral PNA... so why not ask the question? Perhaps you prefer that we focus our clinical research on exciting and novel questions like dose escalation... dose de-escalation... hyperfractioation... hypofractionation... bigger fields... smaller fields... etc...
I disagree. It will likely be a bust, but there are legit pre-clinical and clinical data supporting low dose RT in the treatment of severe viral PNA... so why not ask the question? Perhaps you prefer that we focus our clinical research on exciting and novel questions like dose escalation... dose de-escalation... hyperfractioation... hypofractionation... bigger fields... smaller fields... etc...
Now on the other hand people dug up data from the 30's to use in the 40's. And then dug up data in the 40's to use in the 1950's... etc... and in the 1980's and 1990's ~90% of that thinking was still carried through. And most of that "data" is still in use today! If we didn't (constantly) dig up old (non-randomized data) data from a ~century ago we wouldn't have a specialty. (There is no randomized data that the main tool now in use in modern rad onc, the linac, is clinically superior/inferior to what it replaced e.g. The ubiquitous 6MV beam was meant to be cobalt-y, and so on, and so forth.)
I'm all for a derm vs rad onc battle royale, too.
I actually agree with Weichselbaum here. We are digging up data from the 40s (30s?) to actually treat ventilated patients with 100 cGy? I'd rather turf war the derms and use XRT for acne. Perhaps a SRS FFF with Frame (can let derms put on if they are salty) and fused with post-contrast 7T MRI seq. (gotta use the best) to ensure we use everything.
Calling it a "phase II trial" does not make it more legitimate.
After this is all over, then yes, why not do some more up to date pre-clinical studies and phase 1 analyses on other viral patients and then we can talk about actually treating critical patients on vents during a global pandemic with resource limitations.
I think it's better to randomize ventilated patients than rather "healthy" ones. The mortality on ventilator is very high in this disease.I understand your sentiment. I'm not as excited about the pre-clinical data and think it's not ready for phase 2 randomization on ventilated patients.
I understand your sentiment. I'm not as excited about the pre-clinical data and think it's not ready for phase 2 randomization on ventilated patients. Your points are valid, but just wanted to say I think many of us feel this is a very odd idea that most of us have never used (or want to given all the risk and contamination involved). I just wanted to note that I agree with Weichselbaum on this one and believe this is HIGHLY CONTROVERSIAL. Dr. Weichselbaum's opinion that this is absurd is very rational in light of what is going on and I'm sure other medical specialties will agree shaking their heads at this suggestion.
I know his opinions on residency stuff is off, but on this stuff he is on point. Although maybe I wouldn't be as harsh, I do agree with his warning to us on this stuff:
But you gotta admit, pneumonia data from the 40's does not instill supreme confidence.
I understand your sentiment. I'm not as excited about the pre-clinical data and think it's not ready for phase 2 randomization on ventilated patients. Your points are valid, but just wanted to say I think many of us feel this is a very odd idea that most of us have never used (or want to given all the risk and contamination involved). I just wanted to note that I agree with Weichselbaum on this one and believe this is HIGHLY CONTROVERSIAL. Dr. Weichselbaum's opinion that this is absurd is very rational in light of what is going on and I'm sure other medical specialties will agree shaking their heads at this suggestion.
I know his opinions on residency stuff is off, but on this stuff he is on point. Although maybe I wouldn't be as harsh, I do agree with his warning to us on this stuff:
Then again, when was the last time the US has faced such a deadly pulmonary infection without viable antibiotic therapy? Where else would the data come from?
agree that downside is low to patient, and why not pull out all the stops on ventilated patient given poor prognosis. But how would you control for other medical therapy. Trial should not be done if it limits patients access to gilead or any other drug or convalescent serum.I think it's better to randomize ventilated patients than rather "healthy" ones. The mortality on ventilator is very high in this disease.
I am not convinced that RT will work in this scenario. Yet some rationale is there.
I do not agree with those that think this is insane or that we are hurting patients. The possible toxicity is very low, given the doses involved.
Dr. Weichselbaum's opinion that this is absurd is very rational in light of what is going on and I'm sure other medical specialties will agree shaking their heads at this suggestion.
can’t use antibiotics for a viral infection
"Absurd" & "nutty" (Ralph's words) = magical thinking. This is not magical thinking. This is a legit question (can RT work in pneumonia) and to suggest it's nutty is disingenuous. First off as mentioned there are reports with many patients. Albeit old reports but, still, reports. RT has been "proven" to be anti-inflammatory (dupuytren's, plantar fasciitis, etc); and one of the modes of death from pneumonia is the inflammatory response. Numerous lines of evidence point to a little radiation being good, not bad. Heck we even have data that RT works against viruses (varicella zoster).
Since he called the idea "absurd" & "nutty" Ralph should eat much crow if shown to be incorrect. If the RT were a drug here, drug companies would be all over it. Low risk, high reward.
From Carl Desim MD PhD at WashU on MedNet:Currently, there are three lines of pharmaceutical research to mitigate symptoms in those already infected: Passive immunity (currently this is only provided through convalescent plasma from recovered but there are hopes that one day we will have an active monoclonal antibody, antivirals, and immune-suppressants/modulators.
Hydroxychloroquine falls into the last category. Unfortunately, the limited data available do not support a therapeutic benefit. Pharma is currently trying scores of other immune-suppressants, hoping to see an effect.
Radiation has known anti-inflammatory properties and has actually been used to treat PNA when viable antibiotics were not available.
If RW or any other doctor has a scientific rationale that we should blindly try every immune-suppressant under the sun but not low dose RT (despite the fact that the latter has far more supporting literature), let's hear it. Otherwise, I see no reason why we should care if they call us nutty or shake their heads.
Personally, I only respond to criticism when there is a reason behind it. Absent a rationale, a furrowed brow is just a funny face.
can’t use antibiotics for a viral infection
From Carl Desim MD PhD at WashU on MedNet:
"It's tempting to jump on the hypothesis that the lethality of COVID-19 stems from the body's over-reaction and self-destruction in response to the virus, and that by simply reducing the body's over response we will reduce mortality. In this case, using low dose radiation to reduce inflammatory cytokine release and potentially kill off some of those sensitive inflammatory cells seems like a no-brainer; problem solved.
However, I can think of a compelling alternative hypothesis in which this sort of radiation would make the situation worse, and hasten death. The scenario plays out like this: COVID-19 infects someone who has never been exposed to a similar coronavirus, and has no natural protective immunity. His body tries to fight off the infection with its most effective anti-viral machinery: T and B cells. But since he has no cells presently recognizing any of the COVID-19 antigens, he needs to generate an adaptive immune response from scratch. Given his age, his ability to create a T and B cell response to a new antigen is almost zero. Normally this response takes 2-3 weeks, but this time quickly passes and viral replication continues, exponentially. His body senses this, and resorts to ramping up its next line of defense: macrophages. They engulf as much virus as possible, and secrete more inflammatory cytokines to facilitate viral control, which is sometimes effective.
At this point if we hit them with anti-inflammatory doses of radiation, we quench this last ditch effort at viral control, and although we prevent the cytokine induced toxicity, viral replication now proceeds without any checks, and the patient still dies, perhaps even more quickly.
I think some evidence for this scenario is provided by the observation that high dose steroids do not seem to help COVID-19 patients, even though they do improve pneumonia symptoms in other contexts.
So the answer for me is that I certainly wouldn't do this off trial, and my bet is that low (or high) dose radiation will only exacerbate the problem. My hat is off to those who are trying it out, although ideally some level of animal modeling would be done that points to benefit and not harm before trying it in humans."
A hundred reasons why RT won’t work and maybe only a few why it would. But another basketball analogy: you miss 100% of the shots you never take. Because the “harm” everyone keeps fretting about here is so close to zero, air balling it won’t have tragic downsides... IMHO, despite Rube Goldbergian theories about why it MIGHT.From Carl Desim MD PhD at WashU on MedNet:
"It's tempting to jump on the hypothesis that the lethality of COVID-19 stems from the body's over-reaction and self-destruction in response to the virus, and that by simply reducing the body's over response we will reduce mortality. In this case, using low dose radiation to reduce inflammatory cytokine release and potentially kill off some of those sensitive inflammatory cells seems like a no-brainer; problem solved.
However, I can think of a compelling alternative hypothesis in which this sort of radiation would make the situation worse, and hasten death. The scenario plays out like this: COVID-19 infects someone who has never been exposed to a similar coronavirus, and has no natural protective immunity. His body tries to fight off the infection with its most effective anti-viral machinery: T and B cells. But since he has no cells presently recognizing any of the COVID-19 antigens, he needs to generate an adaptive immune response from scratch. Given his age, his ability to create a T and B cell response to a new antigen is almost zero. Normally this response takes 2-3 weeks, but this time quickly passes and viral replication continues, exponentially. His body senses this, and resorts to ramping up its next line of defense: macrophages. They engulf as much virus as possible, and secrete more inflammatory cytokines to facilitate viral control, which is sometimes effective.
At this point if we hit them with anti-inflammatory doses of radiation, we quench this last ditch effort at viral control, and although we prevent the cytokine induced toxicity, viral replication now proceeds without any checks, and the patient still dies, perhaps even more quickly.
I think some evidence for this scenario is provided by the observation that high dose steroids do not seem to help COVID-19 patients, even though they do improve pneumonia symptoms in other contexts.
So the answer for me is that I certainly wouldn't do this off trial, and my bet is that low (or high) dose radiation will only exacerbate the problem. My hat is off to those who are trying it out, although ideally some level of animal modeling would be done that points to benefit and not harm before trying it in humans."
We know xrt works in some inflammatory conditions like plantar fasciitis, but it’s never been clear to me why. Shouldn’t circulating immune cells from the rest of the body re-enter the area and reinitiate the inflammatory process relatively quickly? We apparently make and consume millions of immune cells every minute.A hundred reasons why RT won’t work and maybe only a few why it would. But another basketball analogy: you miss 100% of the shots you never take. Because the “harm” everyone keeps fretting about here is so close to zero, air balling it won’t have tragic downsides... IMHO, despite Rube Goldbergian theories about why it MIGHT.
A hundred reasons why RT won’t work and maybe only a few why it would. But another basketball analogy: you miss 100% of the shots you never take. Because the “harm” everyone keeps fretting about here is so close to zero, air balling it won’t have tragic downsides... IMHO, despite Rube Goldbergian theories about why it MIGHT.
That is certainly a plausible reason why low dose RT would fail to improve outcomes, however it's worth noting that this argument would also apply to the basket of immuno-suppressant medications currently under investigation for COVID. It's also plausible that, like other cases of PNA, more damage is perpetrated by the inflammatory response than the actual infection.
I agree with Dr. Desim that this should not be done off trial... but disagree with RW that there shouldn't even be a trial, lest we look bad to other disciplines or whatever
Fear of people "shaking their head" has to be the least courageous reason to not ask a scientific question.
Ha I think this is what some surgeons (derms?) refer to RT as... last ditch effort observational study.Why can't we just call it what it is - a latch ditch effort observational study? If the protocol was as honest as you, I might go along with it, but use fluoro.
Harm is there with contamination and spread with an active aerosolizing procedure (vent) but I digress.
Ha I think this is what some surgeons (derms?) refer to RT as... last ditch effort observational study.
It's reasonable to consider a study.
But it's also very reasonable for us in rad onc and others outside to go "huh, ph2 trial quoting 1930s data on active COVID patients on vents?" It is very rational to stop proceeding with scientific studies if it goes against much of what we know. We are bringing in plantar fasciitis as correlation with this????
Also, this is something we can study AFTER the pandemic, as there surely will be COVID patients still afterwards, where then we can run a proper trial perhaps, be fully staffed, and have the PPE necessary. Why do it now under the guise of study that is underpowered, confounded to the moon, thus not being able to obtain reliable results. Can these patients on the vent even consent?
Like I said, let's call it what it is a last ditch effort / hail mary/ observational study where you bring in a fluoro on the unit - much harder to object too. WIth all that is going on, NOW, is not the right time. Just treat if you want to treat.
Bingo. We can't take anyone with more than a NC, and i imagine most freestanding centers are in the same boatWhen is the last time anyone has treated an intubated patient?
It's a **** show bringing them down in best of times
To do it now when staffing is maxed out? Absolute craziness
The only places this can work is medical centers that have attached RO facility and VERY LOW COVID census
When is the last time anyone has treated an intubated patient?
It's a **** show bringing them down in best of times
To do it now when staffing is maxed out? Absolute craziness
The only places this can work is medical centers that have attached RO facility and VERY LOW COVID census
Bingo. We can't take anyone with more than a NC, and i imagine most freestanding centers are in the same boat
Unfortunately, this post is a "miss."A hundred reasons why RT won’t work and maybe only a few why it would. But another basketball analogy: you miss 100% of the shots you never take. Because the “harm” everyone keeps fretting about here is so close to zero, air balling it won’t have tragic downsides... IMHO, despite Rube Goldbergian theories about why it MIGHT.
I treat intubated pts because we see more neglected cancers than we should and it is quite the production. If pt has known covid on study, I would imagine you would have to go overboard with ppe and disinfection for radonc staff. Its one thing an investigational study turns out negative for the pt, but much higher burden of safety for staff. You are asking them to take personal risk for a study?When is the last time anyone has treated an intubated patient?
It's a **** show bringing them down in best of times
To do it now when staffing is maxed out? Absolute craziness
The only places this can work is medical centers that have attached RO facility and VERY LOW COVID census
I treat intubated pts because we see more neglected cancers than we should and it is quite the production. If pt has known covid on study, I would imagine you would have to go overboard with ppe and disinfection for radonc staff. Its one thing an investigational study turns out negative for the pt, but much higher burden of safety for staff. You are asking them to take personal risk for a study?
When is the last time anyone has treated an intubated patient?
It's a **** show bringing them down in best of times
To do it now when staffing is maxed out? Absolute craziness
The only places this can work is medical centers that have attached RO facility and VERY LOW COVID census
Would you need consent from the staff?Also, for patients in dept and those who will use the machine afterwards. You are absolutely correct, as it is one thing to treat a SVC syndrome vs a study patient with COVID-19.
Sure if it is feasible, would be very much in favor because question is so interesting, even if I think it is unlikely to work.There is likely some person receiving radiotherapy while being intubated at any given day/week in the US (think Pediatric RT), and so I would think there is adequate experience in handling intubated patients, albeit concentrated in larger tertiary hospital sites. The concern for treating mechanically ventilated patient is very reasonable but moot, as one can start the trial with unvented pts with primary endpoint of freedom of progression to vent. I absolutely agree that trying to treat ventilated patients at the start would be too challenging, and I, as a proponent of this trial, would add that it may be a different pathophysiology that I am unsure LD IR can deal with. By that point, the lung has so much exudative gunk the mechanism of recovery is to clear up the gunk. And I don't know of any data that shows RT can accelerate clearance of such gunk. Best is a "preVent" trial, as Minesh M. implied.
The resistance to such trial appears to be more logistical rather than scientific. I'm hopeful that the brilliant minds are assessing the feasibility of the logistics. Certainly if it is not feasible and safe, such trial should not be pursued. But lets just say it is deemed feasible, would you naysayers be open to such trial?