RO may have a role in this COVID crisis, but we need a clinical trial.....

[cancer_doc]

Any academics in COVID hotspots got the motivation and balls to start a clinical trial ASAP on use of low dose ionizing radiation (LD IR) to treat COVID patients who are on ventilator or close to needing a ventilator?? Once you are on a vent, it is extremely tough to recover.

Low dose ionizing radiation is known to modulate downstream anti-inflammatory processes. We've used it to treat other benign disease processes (Keloids, heterotopic ossification, etc). I'm not academic anymore, so I have no easy access to start a clinical trial.

Here is a review article on historical use of LD IR to treat pneumonia. How Radiotherapy Was Historically Used To Treat Pneumonia: Could It Be Useful Today?

Yale J Biol Med. 2013 Dec; 86(4): 555–570.
Published online 2013 Dec 13.
PMCID: PMC3848110
PMID: 24348219
How Radiotherapy Was Historically Used To Treat Pneumonia: Could It Be Useful Today?
Edward J. Calabrese, PhD* and Gaurav Dhawan, MPH
Author information Copyright and License information Disclaimer
*To whom all correspondence should be addressed: Edward J. Calabrese, PhD, Professor of Toxicology, Department of Public Health, Environmental Health Sciences, Morrill I, N344, University of Massachusetts, Amherst, MA 01003; Tele: 413-545-3164; Fax: 413-545-4692; Email: ude.ssamu.hploohcs@cdrawde.

Abstract
X-ray therapy was used to treat pneumonia during the first half of the 20th century. Fifteen studies report that approximately 700 cases of bacterial (lobar and bronchopneumonia), sulfanilamide non-responsive, interstitial, and atypical pneumonia were effectively treated by low doses of X-rays, leading to disease resolution, based on clinical symptoms, objective disease biomarkers, and mortality incidence. The capacity of the X-ray treatment to reduce mortality was similar to serum therapy and sulfonamide treatment during the same time period. Studies with four experimental animal models (i.e., mice, guinea pig, cat, and dog) with bacterial and viral pneumonia supported the clinical findings. The mechanism by which the X-ray treatment acts upon pneumonia involves the induction of an anti-inflammatory phenotype that leads to a rapid reversal of clinical symptoms, facilitating disease resolution. The capacity of low doses of X-rays to suppress inflammatory responses is a significant new concept with widespread biomedical and therapeutic applications.
Keywords: pneumonia, X-rays, radiotherapy, hormesis, inflammation, anti-inflammation

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[PhotonBomb]

There’s a long twitter thread about this this morning

 

[DebtRising]

Spoke about it, but didn’t get far due to concern about exposing the department and all the implications that come with it.

 

[RadOncMegatron]

I don’t think it’s the right time for this with a linac. Under mobile fluoride? I think we definitely need more data before trying this very outside the box idea.

 

[Palex80]

There’s a long twitter thread about this this morning

Care to share the link?

 

[Palex80]

I don’t think it’s the right time for this with a linac. Under mobile fluoride? I think we definitely need more data before trying this very outside the box idea.

Start with palliative cases?

 

[PhotonBomb]

 

[RadOncMegatron]

Start with palliative cases?

Should we have these patients enroll in drug therapy trials? I think that may be more urgent. Just thinking out loud. No good answers. Maybe those who fail pharmaceutical intervention can go onto radiation, but in all cases such a poor PS cohort may not be able to show any improvement.

 

[cancer_doc]

at this point, nothing to lose, Ideally focused on a small group. weary to consider after drug therapy trials like chloroquine since there are reports that medication can be radiosensitizing (correct?). ideally hold a concurrent trial separately. At this rate, especially in NYC, NOLA, Detroit, would be doable to enroll patients

 

[PhotonBomb]

NOLA is the worst because they have a bad health care infrastructure to begin with

 

[RickyScott]

This is basically about hormesis? Low doe radiation activation of damage/stress response pathways Which everyone here has been very dismissive?

 

[thecarbonionangle]

Rad onc with balls? Have yet to see it among the catfish turtles that replete out ranks!!

 

[evilbooyaa]

Yeah I would not be enthusiastic. If things that suppressed the immune system worked across the board then steroids should work as well. I would encouragen enrollment or treatment on a number of immune-suppressing agents given systemically rather than focusing on something like whole-lung irradiation.

Academics gonna academic if anyone is serious about evaluating this, and you'd need to have a linac basically dedicated to COVID-19 patients to make this even have a chance, IMO. And we don't know that multiple COVID-19 patients sharing a surface that will not have time to be terminally cleaned in-between will NOT reduce their survival (given some concerns about 'viral load' as a predictor of severity).

And if it does work it'll just be like those chloroquine/azithro data that looks shoddy as hell in terms of selection bias and choice of endponts and all that to anyone who can critically evaluate a study.

 

[RickyScott]

Yeah I would not be enthusiastic. If things that suppressed the immune system worked across the board then steroids should work as well. I would encouragen enrollment or treatment on a number of immune-suppressing agents given systemically rather than focusing on something like whole-lung irradiation.

Academics gonna academic if anyone is serious about evaluating this, and you'd need to have a linac basically dedicated to COVID-19 patients to make this even have a chance, IMO. And we don't know that multiple COVID-19 patients sharing a surface that will not have time to be terminally cleaned in-between will NOT reduce their survival (given some concerns about 'viral load' as a predictor of severity).

And if it does work it'll just be like those chloroquine/azithro data that looks shoddy as hell in terms of selection bias and choice of endponts and all that to anyone who can critically evaluate a study.

Chloroquine sounds really promising based on the stellar id pushing it

The Trumpian French Doctor Behind the Chloroquine Hype

The source of the hopes for a coronavirus cure should raise a lot of red flags.

slate.com

 

[PhotonBomb]

Chloroquine sounds really promising based on the stellar id pushing it

The Trumpian French Doctor Behind the Chloroquine Hype

The source of the hopes for a coronavirus cure should raise a lot of red flags.

slate.com

Trump has a type haha

 

[Chartreuse Wombat]

Talk about long run for a short slide....three months from now we may know that XRT has a role (doubtful)...then the pandemic will be dying and we will be on to other things.

In US
Worse case scenario IMHE is 200K deaths from COVID-19 in 2020; more likely 100K
ACS estimated deaths from cancer is 600K in 2020

Academics gotta academic but count me out of this "new indication for XRT"

 

[FrostyHammer]

Yeah I would not be enthusiastic. If things that suppressed the immune system worked across the board then steroids should work as well. I would encouragen enrollment or treatment on a number of immune-suppressing agents given systemically rather than focusing on something like whole-lung irradiation.

Academics gonna academic if anyone is serious about evaluating this, and you'd need to have a linac basically dedicated to COVID-19 patients to make this even have a chance, IMO. And we don't know that multiple COVID-19 patients sharing a surface that will not have time to be terminally cleaned in-between will NOT reduce their survival (given some concerns about 'viral load' as a predictor of severity).

And if it does work it'll just be like those chloroquine/azithro data that looks shoddy as hell in terms of selection bias and choice of endponts and all that to anyone who can critically evaluate a study.

If I earned a nickel for every IM-based specialist who is actually able to critically evaluate data... I couldn't afford to eat biryani anymore.

 

[wandering star]

Talk about long run for a short slide....three months from now we may know that XRT has a role (doubtful)...then the pandemic will be dying and we will be on to other things.

In US
Worse case scenario IMHE is 200K deaths from COVID-19 in 2020; more likely 100K
ACS estimated deaths from cancer is 600K in 2020

Academics gotta academic but count me out of this "new indication for XRT"

We would hope that in the U.S. and Europe we would be able to curtail deaths promptly, but some parts of the world (e.g. Iran, some countries in Africa) cannot afford to implement effective social distancing measures. Any extrapolation is an educated guess but it's possible that we might see COVID-19 reaching 500 million worldwide within 18 months, with 10 million corresponding deaths.

If a treatment could be provided by a portable x-ray source (nevermind a linac) there could conceivably be large value from an XRT intervention. I know of some efforts to test this idea in academia, but I think other centers should try this as well. Normally multiple parallel studies are a waste of resources, but given our time constraints I think that it should be done now.

I agree that drugs have a higher chance of success overall, but we might as well try multiple ideas and see what works the best.

 

[RickyScott]

Great perspective as always from Derek Lowe

Science | AAAS

blogs.sciencemag.org

 

[thecarbonionangle]

We would hope that in the U.S. and Europe we would be able to curtail deaths promptly, but some parts of the world (e.g. Iran, some countries in Africa) cannot afford to implement effective social distancing measures. Any extrapolation is an educated guess but it's possible that we might see COVID-19 reaching 500 million worldwide within 18 months, with 10 million corresponding deaths.

If a treatment could be provided by a portable x-ray source (nevermind a linac) there could conceivably be large value from an XRT intervention. I know of some efforts to test this idea in academia, but I think other centers should try this as well. Normally multiple parallel studies are a waste of resources, but given our time constraints I think that it should be done now.

I agree that drugs have a higher chance of success overall, but we might as well try multiple ideas and see what works the best.

it is not just other countries. Social distancing is a privilege for those with resources, so is staying home and not working. many poor in the US and minorities will be disproportionally affected.

 

[PhotonBomb]

it is not just other countries. Social distancing is a privilege for those with resources, so is staying home and not working. many poor in the US and minorities will be disproportionally affected.

 

[cancer_doc]

Yeah I would not be enthusiastic. If things that suppressed the immune system worked across the board then steroids should work as well. I would encouragen enrollment or treatment on a number of immune-suppressing agents given systemically rather than focusing on something like whole-lung irradiation.

Academics gonna academic if anyone is serious about evaluating this, and you'd need to have a linac basically dedicated to COVID-19 patients to make this even have a chance, IMO. And we don't know that multiple COVID-19 patients sharing a surface that will not have time to be terminally cleaned in-between will NOT reduce their survival (given some concerns about 'viral load' as a predictor of severity).

And if it does work it'll just be like those chloroquine/azithro data that looks shoddy as hell in terms of selection bias and choice of endponts and all that to anyone who can critically evaluate a study.

Low dose whole lung irradiation at 1Gy is not immunosuppressant per se, especially to the entire body, while modulating local inflammatory pathway, and we do have data, albeit mostly lab studies and very old clinical reports. We know safety of lung RT at such low level. Systemic immunosuppressants may risk knocking out body's ability to fight the virus, which low dose lung IR doesn't.

At such 1Gy, you do not need a linac to treat. A CT-scanner can produce such dose, and we have mobile / intraoperative scanner these days which we can bring the machine to the room and lessen risk to patient / staff / hospital from moving him/her to the linac. Challenge then is you may burn out the tube, which is worth risk if you can help save a few lives.

I don't consider this thinking outside the box, I consider this showing some cojones to bring innovation to the table.

 

[cancer_doc]

Talk about long run for a short slide....three months from now we may know that XRT has a role (doubtful)...then the pandemic will be dying and we will be on to other things.

In US
Worse case scenario IMHE is 200K deaths from COVID-19 in 2020; more likely 100K
ACS estimated deaths from cancer is 600K in 2020

Academics gotta academic but count me out of this "new indication for XRT"

We're going to see the for more than 3 months. Bending the curve lowers the peak, but stretches the base. And this will not be the last SARS-like pandemic we will experience.

 

[Chartreuse Wombat]

We're going to see the for more than 3 months. Bending the curve lowers the peak, but stretches the base. And this will not be the last SARS-like pandemic we will experience.

Perhaps it will last anther three months (no one knows) and I don't dispute that there will be other diseases that crop up but radiation just isn't the answer to most things.

 

[evilbooyaa]

Low dose whole lung irradiation at 1Gy is not immunosuppressant per se, especially to the entire body, while modulating local inflammatory pathway, and we do have data, albeit mostly lab studies and very old clinical reports. We know safety of lung RT at such low level. Systemic immunosuppressants may risk knocking out body's ability to fight the virus, which low dose lung IR doesn't.

At such 1Gy, you do not need a linac to treat. A CT-scanner can produce such dose, and we have mobile / intraoperative scanner these days which we can bring the machine to the room and lessen risk to patient / staff / hospital from moving him/her to the linac. Challenge then is you may burn out the tube, which is worth risk if you can help save a few lives.

I don't consider this thinking outside the box, I consider this showing some cojones to bring innovation to the table.

Go ahead and study it then. Happy to be proven wrong.

 

[deleted941485]

Low dose whole lung irradiation at 1Gy is not immunosuppressant per se, especially to the entire body, while modulating local inflammatory pathway, and we do have data, albeit mostly lab studies and very old clinical reports. We know safety of lung RT at such low level. Systemic immunosuppressants may risk knocking out body's ability to fight the virus, which low dose lung IR doesn't.

At such 1Gy, you do not need a linac to treat. A CT-scanner can produce such dose, and we have mobile / intraoperative scanner these days which we can bring the machine to the room and lessen risk to patient / staff / hospital from moving him/her to the linac. Challenge then is you may burn out the tube, which is worth risk if you can help save a few lives.

I don't consider this thinking outside the box, I consider this showing some cojones to bring innovation to the table.

Definitely gets an A for effort

But honestly we got hydroxychloroquine and azithromycin going with shoddy research but we wanna run a formal clinical trial.

 

[Lamount]

If we are trying every immune-modulator under the sun, why wouldn’t we try XRT? Certainly wouldn’t have the same distribution issues that pharma faces. Happy to hear some are looking at it. Where I work, it’s a hard sell to expose the department to COVID patients... but if there were clinical data, would be happy to have that fight.

 

[evilbooyaa]

Definitely gets an A for effort

But honestly we got hydroxychloroquine and azithromycin going with shoddy research but we wanna run a formal clinical trial.

Remdesivir data looks better, IMO. https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Better than the anecdotal "if you require a ventilator you have an 80% chance of not getting off of it" I've heard, although I'm not aware of any published case series of supportive care alone.

 

[deleted941485]

Remdesivir data looks better, IMO. https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Better than the anecdotal "if you require a ventilator you have an 80% chance of not getting off of it" I've heard, although I'm not aware of any published case series of supportive care alone.

I just saw the medscape article which called the research into that drug “uninterpretable”.

 

[deleted774703]

Spoke about it, but didn’t get far due to concern about exposing the department and all the implications that come with it.

 

[cancer_doc]

Spoke about it, but didn’t get far due to concern about exposing the department and all the implications that come with it.

Low dose IR can be applied using kV CT scanners, and there are mobile CT scanners. Would be a better initial sell if you can bring the treatment to the patient vs bringing pt to the dept..... Ever considered that? I know someone in Mayo who already worked out a protocol using CT scanners and verified with physics. I can help connect you with him.

 

[Palex80]

Is Prof. Weichselbaum always so negative?

 

[deleted774703]

Is Prof. Weichselbaum always so negative?

frequently lol. For once I agree with him though. Our attendings get crapped on at my hospital during tumor boards already. Granted all but 2 are mediocre but still lol

 

[medgator]

. Our attendings get crapped on at my hospital during tumor boards already.

Some of us out in the real world help run ours and are respected by other specialists.

Maybe Ralph should stop being such a negative Nancy

 

[radoncgrad2019]

agree with Ralph on this one.

 

[deleted774703]

Some of us out in the real world help run ours and are respected by other specialists.

Maybe Ralph should stop being such a negative Nancy

glad to hear that. I can say I’ve learned a lot of what NOT to do via residency

 

[RickyScott]

agree with Ralph on this one.

I just have no idea how you would design a trial. Are pts going to be denied Gilead drug or convalescent serum which actually look promising. What would the endpt be- viral load, death? This is a disease with a cfr of .3-.6%- how many pts would you need to treat to show a difference? It simply is not logistically possible.

https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

 

[Palex80]

agree with Ralph on this one.

Thalidomide for myeloma comes into mind...
I am certain some had the same thoughts when it was proposed as a possibility for myeloma. 20 years later we now have a whole class of agents for that disease which has reshaped its entire treatment based on the very idea of using thalidomide.

Another long forgotten drug, which experienced a revival based on old data and was put to use again is Bendamustine.
Developed in the 60s in Eastern Germany, forgotten for decades and picked up again almost 50 years later, now standard of care for NHL and CLL.

 

[Palex80]

I just have no idea how you would design a trial. Are pts going to be denied Gilead drug or convalescent serum which actually look promising. What would you endpt be? This is a disease with a cfr of .3-.6%- how many pts
Would you need to treat to show a difference?

https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Actually I would allow the patients to receive any other care (outside of a trial) and then simply irradiate them on top.

If a drug trial was available, I would not open the radiation therapy trial at that site.

 

[deleted774703]

Actually I would allow the patients to receive any other care (outside of a trial) and then simply irradiate them on top.

If a drug trial was available, I would not open the radiation therapy trial at that site.

How would you know the RT has any effect then?

Unless you do drug +/- RT

seems like a waste of time

 

[RickyScott]

Actually I would allow the patients to receive any other care (outside of a trial) and then simply irradiate them on top.

If a drug trial was available, I would not open the radiation therapy trial at that site.

Still given the low death rate you would need huge numbers
Drug trials and convalescent serum trials are opening everywhere. Even my hospital is offering Gilead drug- and I am sure that Gilead would not allow delivery of xrt

 

[Neuronix]

if I told you all I had an antimalarial drug on which only observational data is a available that is 70 years old with no scientific basis

Hydroxychloroquine ?

 

[RickyScott]

Thalidomide for myeloma comes into mind...
I am certain some had the same thoughts when it was proposed as a possibility for myeloma. 20 years later we now have a whole class of agents for that disease which has reshaped its entire treatment based on the very idea of using thalidomide.

Another long forgotten drug, which experienced a revival based on old data and was put to use again is Bendamustine.
Developed in the 60s in Eastern Germany, forgotten for decades and picked up again almost 50 years later, now standard of care for NHL and CLL.

I am not knocking the idea. I am probably the only regular poster who believes that there may be something to hormesis. I just don’t see how you could implement this for corona virus. Myeloma 20’years ago was fatal within 2-3 years, so easy to see a signal. Cll and nhl, you can also see a signal if tumors are shrinking, counts improving.
Much easier to give plaquenil to the thousands needed to treat to see a difference, than low dose xrt.

 

[cancer_doc]

I just have no idea how you would design a trial. Are pts going to be denied Gilead drug or convalescent serum which actually look promising. What would the endpt be- viral load, death? This is a disease with a cfr of .3-.6%- how many pts would you need to treat to show a difference? It simply is not logistically possible.

https://www.nejm.org/doi/full/10.1056/NEJMoa2007016

Primary endpoint should be freedom from progression to ventilator for hospitalized patients showing high-risk features or perhaps include those already on ventilator and endpoint is vent recovery. Once you are on ventilatory, mortality rate is alarming (50-80%). We're not talking about treating every COVID + pt ,but only high-risk hospitalized pts, so I don't think you need that many people to start a trial. No need to worry about viral load, as this is a local symptom treatment.

honestly, would love to see an LD IR trial separate from Gilead, especially if there is a hotspot site unable to have access to remdesivir, but otherwise likely should wait till remdesivir data comes out. If it shows negative or modestly positive results, then can consider remdesivir +/- LD lung IR. I think we will see remdesivir results fairly soon.... I would worry about using this with Plaquenil since there may be radiosensitivity associated with that drug.

 

[Palex80]

How would you know the RT has any effect then?

Unless you do drug +/- RT

seems like a waste of time

This is precisely the design of a randomized Phase III trial.

But before coming to that, you would need some kind of Phase I/II to establish safety and get any potential signal for efficacy.
That's probably the tricky part. What to assume and what to expect...

 

[cancer_doc]

I am not knocking the idea. I am probably the only regular poster who believes that there may be something to hormesis. I just don’t see how you could implement this for corona virus. Myeloma 20’years ago was fatal within 2-3 years, so easy to see a signal. Cll and nhl, you can also see a signal if tumors are shrinking, counts improving.
Much easier to give plaquenil to the thousands needed to treat to see a difference, than low dose xrt.

Hormesis is a cytoprotective hypothesis. While LD IR has been linked to this hypothesis and to inflammatory-pathway modulation, this is unrelated to Hormesis as we are only discussing whether LD IR can prevent or reverse an acute process (ARDS mediated by cytokine storm) that causes some high-risk hospitalized COVID pts to progress to mechanical ventilation.

 

[Palex80]

Still given the low death rate you would need huge numbers
Drug trials and convalescent serum trials are opening everywhere. Even my hospital is offering Gilead drug- and I am sure that Gilead would not allow delivery of xrt

Of course, if a competing drug trial is running, it's a no-go.

The death rate is not low. Not if you target the right population. Frankly, I only see some rationale for RT in patients with severe respiratory symptoms, meaning the ones that are on the ventilator or on their way to the ventilator. This of course makes logistics tougher.
On the other hand, reported mortality rates of patients on the ventilator are in the range of 80% according to some Chinese data.
Now, that's China and perhaps too late intubated or too comorbid or whatever. But still, a 75 year old with a few comorbidities and COVID needing a ventilator has a high of not getting off that ventilator.
I would also only allow patients to enter the trial that have some kind of documented hyperinflammation. That's not so easy to filter out, but there are some biomarkers you can use, like IL-6 and so on... Withour hyperiflammation and severe pneumonia, I do not see how RT would work.
The tricky thing here again is that you should not wait too long, otherwise RT might be too late to change anything. It's a bit like these chronic inflammatory conditions we irradiate with 6 x 0.5 Gy. Patients who have had symptoms for many years tend to respond less well than those who have had them for months or a year or so.

 

[Palex80]

I am not knocking the idea. I am probably the only regular poster who believes that there may be something to hormesis.

I don't think it has to do with hormesis. It's immunomodulatory.

 

[evilbooyaa]

I.... agree with Ralph?

Oh, god, what has become of me.

 

[deleted774703]

This is precisely the design of a randomized Phase III trial.

But before coming to that, you would need some kind of Phase I/II to establish safety and get any potential signal for efficacy.
That's probably the tricky part. What to assume and what to expect...

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