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

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I don't think it has to do with hormesis. It's immunomodulatory.
Sirtuin activation, the pressunrd mechanism of hormesis is highly immunomodulatory.

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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....
 
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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
 
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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


Agree, definitely more of a logistical challenge than radiation toxicity issue as you originally stated.

I've discussed some solutions to the logistical challenges in prior posts- such as patient selection, exclude vent patients and those nonvented at high risk. then the dilemma is if you loosen pt eligibility, you increase chance of treating patients who may not have really needed LD IR.

Bring treatment to patient instead of bringing patient (and care team) to treatment: Use mobile CT scanner and treat in room. then the question is developing protocol to minimize staff exposure. I think this is the most workable routine

The most practical option is to find sites that are not at overcapacity but still have moderate volume to work in protocol.
 
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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......
 
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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

Well, ethics are ethics and you should not rush into a Phase III randomized trial if you have no pre-existing evidence from Phase I/II.

You will have to make up a figure of mortality risk with s.o.c. and assume that RT will make that figure better. If you end up with a worse figure, it's over.

For example:

30 days mortality with s.o.c. is 70%, with RT it's going to be 50%.
If you end up with 90%, RT is dead as a concept (like the patients).
If you turn out with something like 60%, then perhaps you can pursue it further.
 
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.
The data are there, but they are not there for COVID patients with pneumonia.
They are there for (mostly) lung healthy patients (often kids) with lung metastases. Not the same group.
From an ethical point of view, you should try to show first that RT will not harm patients with pneumonia. That is at least my opinion.

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??
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...
 
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A multi-institutional study may be in the works.... This from is posted on 4/18/2020 on another website.


"This is a joint reply from a team developing a prospective trial to answer this question:
Minesh Mehta, Arnab Chakravarti, Walter Curran Jr, James Fontanesi, Vinai Gondi, Michael Kasper, Deepak Khuntia, Rupesh Kotecha, Ramesh Rengan, Leland Rogers, Charles B. Simone II, James Welsh, George Wilson

This is a rather erudite question, and we appreciate the opportunity to convey plans for a trial that have lately emerged from vintage radiation therapy reports, aligned with its modern radiotherapy usage for an array of benign diseases, and an emerging understanding of “immunoradiobiology”. COVID-19 has, to date, infected over 2.3 million people worldwide with more than 158,000 deaths. Crude mortality estimates range from 1 to 6%. Most patients exhibit mild symptomatology, but approximately 15% develop pneumonitis and 5% require ventilatory support, for a syndrome superficially akin to ARDS. The overall mortality rate for such patients is approximately 50%, while for those ventilated 5 or more days, for the elderly, and for those with consequential co-morbidities, mortality rates approach 80 to 90%. The pathogenesis of COVID-19 pneumonitis appears to involve a cytokine storm with elevated pro-inflammatory cytokines such as IL-6 and TNFα among many others, leading to an onslaught of neutrophils and macrophages, diffuse alveolar damage and respiratory failure. This is where a potential opportunity for low-dose radiation therapy emerges.

A multi-institutional group including, but not limited to, members from the William Beaumont Hospital, Dignity Health, Phoenix, Emory, Loyola University, Lynn Cancer Institute, Boca Raton, Miami Cancer Institute, New York Proton Center (and Memorial Sloan Kettering Cancer Center), Northwestern Medicine, Ohio State University, University of Washington, and others, are in the process of finalizing a signal seeking, randomized, Phase 2 clinical trial exploring the use of low-dose radiotherapy to treat COVID-19 induced pneumonitis.
Preceding early antibiotic therapy with sulfonamides in the late 1930s, radiotherapy successfully treated pneumonia and other infectious diseases at doses far below those required to extirpate the infectious agents themselves. As briefly described in the Kirby and MacKenzie letter published earlier this month in the Green Journal, historical reports described effective management of pneumonia/pneumonitis, including atypical or viral pneumonias, as described in the US Navy Bulletin (Correll and Cowan: United States Naval Medical Bulletin 1943;41(4):980-7) using low-dose radiotherapy in the 30-100 cGy range. In the US Naval Medical Bulletin, the key findings were as follows:
  1. The clinical findings and response to treatment in a series of 155 patients with atypical (viral) pneumonia were reported.
  2. In 23 of these patients, x-ray therapy alone was used, and within 4 days, 96% of these patients responded; the febrile period, the total number of sick days and the number of days to improvement seen on chest x-ray, was halved in these patients compared to those not receiving x-ray therapy.
  3. In 9 patients, who had failed to respond to all available treatments for 30 days or more, x-ray therapy was used and 7/9 cleared their pneumonic processes within 4 days.
  4. Treatment was 112 roentgen units (r) to the involved lobe, repeated once at 24 hours when needed, never more than two doses, highlighting the effect of low-dose RT during an acute phase of respiratory disease with inflammation.
A recent publication by Calabrese and colleagues (Human and Experimental Toxicology, May 6 2019) summarizes the historic context and proposes possible mechanisms of action; we have reproduced the verbatim summary from that publication below:

“During the early part of the past century, hundreds of clinical studies involving more than 37,000 patients were conducted that showed radiotherapy (RT) to be a successful and safe alternative to drug therapy for the treatment of many diverse inflammatory conditions and diseases (e.g. tendonitis, bursitis, arthritis, and serious inflammatory lung conditions). Data from these studies were collected and analyzed with the intent of estimating an optimal dosing range for RT that would induce an efficacious treatment response. RT was reported to be frequently effective after only a single treatment, with a rapid (within 24 h) and often long-lasting (from months to years) relief from symptoms. Over a two-decade span from the 1920s to the 1940s, the therapeutic responses to a single RT treatment consistently improved as the dosing for multiple ailments decreased over time to between 30 and 100 r. These findings are significant and in agreement with a number of contemporary reports from Germany where RT has been commonly and successfully employed in treating ailments with an inflammatory origin. A proposed mechanism by which RT mitigates inflammation and facilitates healing is via the polarization of macrophages to an anti-inflammatory or M2 phenotype.”
In addition, we suggest that there are several additional proposed mechanisms by which RT mitigates inflammation and facilitates healing, including inducing apoptosis in radiosensitive neutrophils and activated T cells, and inhibiting endothelial/leukocyte interaction resulting in reduced trafficking of infiltrating immune cells.

Previously, in 2013, the same group had addressed the historic use of RT for atypical and bronchopneumonia published in the Yale Journal of Biology and Medicine. The efficacy of radiotherapy was described as similar to that of sulfonamides. They reported that low-dose RT decreased mortality from 30% to 5-10%. We present a verbatim summary excerpt from that paper below:

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.”

In the course of normal medical progress, one would develop animal models, get a better understanding of mechanisms of action, thoroughly investigate a dose-response relationship, then conduct a pilot safety study, all before developing a small phase 2 signal-seeking trial and ultimately proceeding with a randomized, ideally sham-irradiation control phase 3 trial.
In a pandemic, when hundreds to thousands are dying on a daily basis, the call to action is more urgent. Rapid yet scientifically robust responses, commensurate with other expedited and radical approaches to natural disasters and pandemics, are appropriate and required under such dire circumstances. In this context, the group has already developed drafts of a multicenter clinical trial. One version of this concept (yet to be finalized), proposes the following broad-scope strategy:

The basic design of this trial, referred to as the “PreVent Trial”, is to select patients with pneumonia who have tested positive for SARS-CoV-2 viral infection, and whose respiratory status has declined to the point of hospitalization and initiation of supportive respiratory measures. A small initial cohort of patients would be randomized, 2:1 to standard of care with or without low-dose radiotherapy, which would be a single thoracic radiotherapy dose of either 50 cGy or 100 cGy, using the simplest of techniques, with full PPE and decontamination measures in place. The response of these patients in the first 15 days would allow selection of the most effective radiation dose (“pick-the-winner strategy). An additional approximately 60 patients would be enrolled to the more-effective dose arm, allowing approximately 80 patients on this arm.
The appropriate control group would be selected, ideally through a 2:1 randomization, if feasible, and if not, through the collation of a matched historic control. The control and treated groups (after propensity matching, if a historic cohort is used, and with stratification if a randomized design is pursued) would be compared for the primary end-point, which could likely be a composite, including variables such as 2-month mortality (estimated at 30% for the control group), plus the rate of mechanical ventilation (estimated at 30% for the control group), plus the rate of mechanical ventilatory support exceeding 7 days (estimated at 20% for the control group). The goal would be to demonstrate if radiotherapy could halve this to a cumulative total of 40% or less. Additional secondary goals would be to determine whether post-recovery lung function is superior in irradiated patients, and whether we could identify blood and radiologic markers permitting selection of patients most likely to benefit from a such a strategy. The future goal (not embedded in this trial yet) would be to test the most effective pharmacologic agent identified from on-going clinical trials singly, versus in combination with x-ray therapy, in a phase 3 randomized trial.

A parallel trial for intubated patients is also being nested within this protocol, with the goal of achieving faster extubation.

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."
 
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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."
Good dovetailing of Dickens and respiratory issues...
 
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Ah the famous Dickens quote, the perfect summary of our field. Who knew!!
 


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.
 
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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 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...
 
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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'm all for a derm vs rad onc battle royale, too.
 
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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 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.
 
There is a VA study (randomized Phase II of low dose RT - 0 vs. 50 or 100cGy ) in the works as well.
 
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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 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:

 
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.

Battle Royale for the ages!

But you gotta admit, pneumonia data from the 40's does not instill supreme confidence.
 
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.

The photons in the 30's and 40's are no different than today's photons, unless somehow Physics decided to change itself in the past century. unlike the 30's/40's, we now have more certainty that the 100cGy we deliver is actually 100cGy. One can argue whether the accuracy of a clinical diagnosis of pneumonia and resolution of the pneumonia back in the 30's and 40's is up to par with current standards, but there are multiple modern lab studies that have validated inflammatory-modulating effects of LD IR as well as clinical studies on treating non pneumonia-related inflammatory processes.

We are about 13K shy of matching the number of American deaths in the entire Vietnam war, in a span of just 3 months, so I think it's worth finding any way to fight this in all fronts (pharmaceutical, biomedical device, and yes, radiotherapy) and getting into it now than later.
 
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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 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.
 
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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:



Ralph expects radoncs to be focused on antivirals? Huh?

Obviously our focus would be on RT and that certainly doesn’t detract from others outside of our field looking at developing antivirals
 
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But you gotta admit, pneumonia data from the 40's does not instill supreme confidence.

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?
 
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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:


"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.
 
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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?

can’t use antibiotics for a viral infection ;)
 
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.
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.
 
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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.



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.
 
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can’t use antibiotics for a viral infection ;)

lol true, while RT was used for both bacterial and viral pneumonia, i probably should have used the more generalized term of "anti-microbial" which also includes anti-virals like tamiflu
 
"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.

Definitely should eat that humble pie if it works, but aren’t these trials underpowered from the start? The data from these trials you know will be inconclusive. So sounds like a "better than nothing" kind of rationale.

If this is all last ditch effort stuff we are basing off early 1900’s data (we are assuming that the data is good given all limitations of diagnosis & collection at that time. I think this is just when statistical testing, is starting) Is this data better than hydroxychloroquine + azithromycin data? We are also saying this is a better option than any other drug trial like remdesivir would be.

Part of the nuttiness comes into play because of the current clinical situation with all the resource limitations, confounding from the start to limit reliability of the data, etc. It’s not peacetime right now. These trials also would need to collect as adverse effects contamination and delays on other patients and staff due to treating in a LINAC. Not to mention is this being used first line, second line, third line?

I’m ok if we say “hey last ditch effort, so what do we got to lose” then use flouro (with its flaws) to try and get that dose instead of bringing these critical patients into a LINAC. Obviously collect that data and try to glean something from it, but not pretend this is a great ph2 trial.
 
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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.
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."
 
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Do have concerns about relative importance of cytokine storm here. Obviously there is a lot of inflammation going on as lungs go down the toilet, like amyloid with Alzheimer’s (Getting rid of amyloid doesn’t seem to help), but It’s really a leap of faith to think controlling inflammation will significantly improve outcome. Certainly could do the opposite as you point out.

For all the pics of young vibrant lives lost, this remains disease that vast majority of deaths are older (hypertensive and obese) who are not as capable at mounting inflammation response. Saw that VA study yesterday suggests that plaquenil causes worse outcomes.

1918 flu killed by cytokine storm- vast majority of deaths mostly confined to adolescents and people in 20s.
 
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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."

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.
 
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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.
 
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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.
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.

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.
 
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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.

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.
 
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.
 
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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.

"it is very rational to stop proceeding with scientific studies if it goes again what we know"... and what, exactly, do we know? We know that intubated COVID patients have a horrible prognosis. We know that THERE ACTUALLY ARE DATA showing that RT works for untreatable viral PNA... Don't confuse what we know with what you fear.


"Also, this is something we can study AFTER the pandemic"
Sure, that would be easier and less risky to us... but then again, if the study is positive, we miss an opportunity to help countless people. Perhaps it is this mentality that causes other specialties to disrespect us... that we are too afraid to be innovative.
 
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
 
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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
 
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All this talk is honestly due to academic rad oncs losing volume leading to WAY too much free time on their hands

I've been keeping track of the COVID radonc publications recently and they are mainly so stupid. Its just another scheme to pad stats

Look at this one: RT guidelines for GBM at MDACC.

Are you fing kidding me? Give hypofxn b/c of COVID? Thank you for summarizing the Roa and Malmstrom data that any competent rad onc already knows

 
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When COVID-19 hit it was like a race among a number of academics to write "recommendations" quickly and get free red journal articles. A bunch of institutions jumped into that fray. I guess they ran out of papers to write about Student Doctor Network spreadsheets.
 
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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

Agree with @RadOnc16 and @medgator.

@Lamount I understand where you are coming from. Makes sense and you are obviously a sharp mind (impressed by the Bayes comments). Perfectly rational in your thinking. I just disagree.

What many of us think, including Weichselbaum, is that this is "Absolute craziness" in the words of @radoncdoc16 I also think this has to be recognized as a rationale thought process that is endorsed by many of your peers. Many of us would refuse to open this in our center and absolutely oppose it based on good scientific rationale.

Please keep in mind, I have said that I might support the idea of treating these patients with fluoro on an observational study (or just treat them if you want too!). No point in a poorly done randomized study. Why not collect ph 1 data, as safety in COVID-19 ventilated patients in unknown, so that we can then consider this later on if a second wave hits?

Data is very sparse, old data likely confounded, and this is really an unprecedented treatment course (ventilated viral PNA & XRT seriously...). Just call it a last ditch effort and be done with it!
 
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.
Unfortunately, this post is a "miss."

The "100% of shots" quote was Wayne Gretzky and thus a hockey analogy.

If you "air ball" on the rink, you're in real trouble. Some may say malpractice.

Pedantic ribbing aside, I agree with your your point entirely.
 
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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?
 
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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?

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.
 
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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

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?

And one thing the trialists should consider is using mobile CT scanners in additional to linacs..
 
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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?
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.
 
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