FLASH radiotherapy: too good to be true?

[Lamount]

https://www.thegreenjournal.com/article/S0167-8140(19)30360-3/pdf

---

Members don't see this ad.

 

[scarbrtj]

Either the results have been 1) misinterpreted by people unintelligent, 2) misreported by people untruthful, or 3) are not too good to be true. So roughly there's a 67% chance they're too good to be true But I hope they're true. I get a bit of anxiety thinking about if they're true. If REALLY true, then all the curative treatments I've given with my TrueBeam or whatever today were substandard. I hate substandard.* But my center could not easily, if at all, afford a new machine tomorrow.

* I have been recently talking to a friend at a proton center where most of the institution's H&N patients are being sent. First, I was a little surprised that they're doing chemoRT with protons and doing curative HNSCC treatments with protons. Second, I was interested to hear that it seems most people are agreeing the proton HNSCC patients have less side effects. Third, I kind of felt the pang of jealousy with the preceding statement. I want to give treatments with less side effects too!

 

[Krukenberg]

Either the results have been 1) misinterpreted by people unintelligent, 2) misreported by people untruthful, or 3) are not too good to be true. So roughly there's a 67% chance they're too good to be true But I hope they're true. I get a bit of anxiety thinking about if they're true. If REALLY true, then all the curative treatments I've given with my TrueBeam or whatever today were substandard. I hate substandard.* But my center could not easily, if at all, afford a new machine tomorrow.

* I have been recently talking to a friend at a proton center where most of the institution's H&N patients are being sent. First, I was a little surprised that they're doing chemoRT with protons and doing curative HNSCC treatments with protons. Second, I was interested to hear that it seems most people are agreeing the proton HNSCC patients have less side effects. Third, I kind of felt the pang of jealousy with the preceding statement. I want to give treatments with less side effects too!

Compound this with the fact that cyclotron-based proton beams are, at the moment, the only means to treat non-superficial rumors with FLASH. A radically different linac design is under development currently though that may be able to do IMRT FLASH.

 

[evilbooyaa]

Seems like a cool idea. No idea how it works but I don't really care as long as it does work. Look forward to some human safety results upcoming.

What if we could deliver all the radiation a tumor needed in a single treatment, even in big areas, without having to worry about the side effects?

 

[Gfunk6]

Flash! Ah-ah
Savior of the universe
Flash! Ah-ah
It'll save everyone of us
Flash! Ah-ah
It's a miracle
Flash! Ah-ah
King of the impossible
It's for every one of us

 

[RollTideRadOnc]

* I have been recently talking to a friend at a proton center where most of the institution's H&N patients are being sent. First, I was a little surprised that they're doing chemoRT with protons and doing curative HNSCC treatments with protons. Second, I was interested to hear that it seems most people are agreeing the proton HNSCC patients have less side effects. Third, I kind of felt the pang of jealousy with the preceding statement. I want to give treatments with less side effects too!

I would be cautious interpreting anecdotal word that protons are better for HNSCC unless there're robust data showing this the case. As far as I know, there are no such prospective or high quality data. Just like everyone "knew" that protons would be better for prostate, the case of protons for HNSCC may also prove to be spurious (which is in no way to cast aspersions on our well meaning colleagues who work with protons). And the financial toxicity for patients is not insignificant.

In my opinion, do you know what's likely better than protons for HN cancer? Appropriate de-escalation.

 

[medgator]

In my opinion, do you know what's likely better than protons for HN cancer? Appropriate de-escalation.

Agree, although to be fair, there isn't much "prime time" data there either, at least nothing I'd hang my hat on in community practice.... Outside of maybe being ok with weekly instead of Q3 weeks cisplatin for my p16/hpv+ pts, I'm not doing anything different at this point

 

[thecarbonionangle]

people who routinely treat with protons anecdotally assure you that their prostate and head and neck patients do better than photons. For prostate I have not seen any good data. We will see. With head and neck plans, sometimes they look pretty nice sparing the oral cavity or some specific area, but it is not generally always better, case by case for sure.

 

[evilbooyaa]

I would be cautious interpreting anecdotal word that protons are better for HNSCC unless there're robust data showing this the case. As far as I know, there are no such prospective or high quality data. Just like everyone "knew" that protons would be better for prostate, the case of protons for HNSCC may also prove to be spurious (which is in no way to cast aspersions on our well meaning colleagues who work with protons). And the financial toxicity for patients is not insignificant.

In my opinion, do you know what's likely better than protons for HN cancer? Appropriate de-escalation.

That's all in HPV+ Oropharynx (appropriately). There's much more to H&N cancer than HPV+ Oropharynx. I see more H&N (definitive or adjuvant) that is NOT HPV+ OPhx by like a 5:1 ratio.

I don't disagree with your point, just saying. And 1016 was a step back IMO. I'm not doing any dose de-escalation off protocol without a very good, appropriately powered phase III.

In regards to the first point - completely agree. Anecdotes for protons in the current era, given how long it's been around, is absolute non-sense. Show me the money (published data).

 

[OTN]

people who routinely treat with protons anecdotally assure you that their prostate and head and neck patients do better than photons. For prostate I have not seen any good data. We will see. With head and neck plans, sometimes they look pretty nice sparing the oral cavity or some specific area, but it is not generally always better, case by case for sure.

Anecdotal data is not data.

 

[xrthopeful]

for head and neck - now that more people are doing IMPT, some of the plans look good for sure on paper, but in terms of the high-moderate dose volume, not that different than a tight VMAT modern plan. Yeah, the 5-10 Gy IDL and such will be there on a photon plan that you don't see on the proton plan. Hard to know if it matters.

for pelvis - just don't think proton will ever help.

 

[thecarbonionangle]

Anecdotal data is not data.

well yeah certainly not, that was my point. There's little data. All the plans I see are pretty nice, but data is important

 

[evilbooyaa]

well yeah certainly not, that was my point. There's little data. All the plans I see are pretty nice, but data is important

I continue to have concerns that what is shown on a pretty proton plan is not what is actually being delivered due to inherent uncertainties of proton (and other particle) therapy. Otherwise all these dosimetric improvements should have shown some clinical benefit, somewhere, long ago.

 

[thecarbonionangle]

I continue to have concerns that what is shown on a pretty proton plan is not what is actually being delivered due to inherent uncertainties of proton (and other particle) therapy. Otherwise all these dosimetric improvements should have shown some clinical benefit, somewhere, long ago.

cautious of particle therapy as well for that reason. Especially in the head and neck there's lots of air in sinuses and open spaces. The uncertainties make it doubtful to me that is what is actually being delivered, although they assure you that is what happening and they have taken all those factors into account when I have asked.

As someone already pointed out, forgot who, the recent carbon ion therapy papers from japan in head and neck have in some cases larger nodal failure rates, also bad toxicities like blindness in some patients. The angle still needs to be worked out.

 

[scarbrtj]

for head and neck - now that more people are doing IMPT, some of the plans look good for sure on paper, but in terms of the high-moderate dose volume, not that different than a tight VMAT modern plan. Yeah, the 5-10 Gy IDL and such will be there on a photon plan that you don't see on the proton plan. Hard to know if it matters.

for pelvis - just don't think proton will ever help.

A FLASH DVH and an IMRT DVH can ostensibly look exactly the same, but it's claimed the FLASH DVH correlates with less side effects than the IMRT DVH does. Perhaps this is true in protons too. I think we just don't know--for sure.

Otherwise all these [proton] dosimetric improvements should have shown some clinical benefit, somewhere, long ago.

Amen to that.

 

[ramsesthenice]

We will have to wait to see how it pans out but I think there is a fundamental (and theoretical) difference between FLASH and conventional radiotherapy worth mentioning. Preclinically, there is reasonable evidence that normal tissues are, for whatever reason, relatively insensitive to RT delivered using short bursts with an exceedingly high dose rate. Tumors, on the other hand, appear to sustain high levels of oxidative damage. A lot of the classic radiobiologists and redox/metabolism folks are really excited about it and have been for a while. One of the biggest potential advantages of FLASH radiotherapy is that normal tissue avoidance may not be as critical as it is with conventional dose rates.

Again, not ready for prime time. Its way to early to decide its a game changer. If it pans out it could be. Or it could be yet another magic bullet that misses the mark.

 

[RollTideRadOnc]

One of the biggest potential advantages of FLASH radiotherapy is that normal tissue avoidance may not be as critical as it is with conventional dose rates.

Awesome! Let's get out our crayons and do some nice 2D radiotherapy since avoiding normals will be a thing of the past!

 

[evilbooyaa]

A FLASH DVH and an IMRT DVH can ostensibly look exactly the same, but it's claimed the FLASH DVH correlates with less side effects than the IMRT DVH does. Perhaps this is true in protons too. I think we just don't know--for sure.

Right. I'm going to have the same standards for this as I do for protons. Show me clinical toxicity outcome data, ideally in humans. I look forward to it. Could you imagine how awesome this would be for patients? What if chemotherapy wasn't the magic bullet? What if we could just do FLASH radiation to the entire body like taking a picture of somebody with a camera and it selectively killed every cancer cell but not normal tissue? No need for surgery or medical oncology.

Of course, this is unlikely to happen (just like all those medical oncology magic bullets), but it's a cool idea.

 

[scarbrtj]

implied

What if we could just do FLASH radiation to the entire body like taking a picture of somebody with a camera and it selectively killed every cancer cell but not normal tissue? No need for surgery or medical oncology or 4-year radiation oncology residencies

 

[SneakyBooger]

But my center could not easily, if at all, afford a new machine tomorrow.

One of the physicists I work with said most Linacs could be retrofitted to perform FLASH.

But I have no idea if that is true so I am just going to start that rumor.

 

[Gfunk6]

If FLASH really pans out like the preliminary data suggests, it will be hilarious to see people continue to justify proton/carbon/MRILinac when a 25 year old accelerator with an amped up dose-rate can do a better job in fewer fractions with less toxicity.

I went to a FLASH symposium earlier this year and apparently older linacs can be retrofitted to do this.

 

[Lamount]

If FLASH really pans out like the preliminary data suggests, it will be hilarious to see people continue to justify proton/carbon/MRILinac when a 25 year old accelerator with an amped up dose-rate can do a better job in fewer fractions with less toxicity.

I went to a FLASH symposium earlier this year and apparently older linacs can be retrofitted to do this.

Is that with electrons or photons? I heard that this was possible only in electron mode as the dose rate of electrons have to be orders of magnitude higher to account for inefficiency of the bremsstrahlung conversion to X Rays (I.e > 95% electron fluence is lost to heat). Are the older LINACs capable of producing an electron current high enough to support X Ray dose rates > 40 Gy/s?

 

[gmsquid]

The other caveat to flash is presumably you’ll still have to modulate the beam to do imrt so you’d either have to do mlc movements faster than the dose rate or do step and shoot imrt with a break to start and stop the beam between each segment. I highly doubt that you could do flash with 2D and avoid all the toxicity you would with imrt. Who knows though

 

[wandering star]

Is that with electrons or photons? I heard that this was possible only in electron mode as the dose rate of electrons have to be orders of magnitude higher to account for inefficiency of the bremsstrahlung conversion to X Rays (I.e > 95% electron fluence is lost to heat).

Yes, that's correct. Older linacs have been converted to FLASH mode in a preclinical animal setting, but this only works with electrons, and it's done basically by removing the metal layer that converts electrons to x-rays (which, as you point out, is incredibly inefficient). I think that even if the linac had a mode that would give you 1000x more power for free, you still couldn't do FLASH with x-rays because the metal would melt before the treatment is finished.

The other caveat to flash is presumably you’ll still have to modulate the beam to do imrt so you’d either have to do mlc movements faster than the dose rate or do step and shoot imrt with a break to start and stop the beam between each segment. I highly doubt that you could do flash with 2D and avoid all the toxicity you would with imrt. Who knows though

This was a question asked to Bill Loo (the clinician leader of a prototype FLASH x-ray platform) this year at AAPM, and his opinion was that you really would want some of both worlds: FLASH capability along with spatial modulation a la IMRT. Obviously we are operating in a data free zone here but if you had to pick and choose one of FLASH and IMRT, I imagine the winner would be disease specific.

Their design for the x-ray FLASH would avoid MLC motion but it sounds like it's in a very early stage (basically a blueprint, with some testing of individual components they want to build).

 

[Palex80]

1. We know way too little about the radioniology around FLASH radiotherapy. If the theory upholds in clinical practice it will certainly radically change our entire field. All the Rs of radioniology will become rather obsolete and we will be treating patients with new regimes. IF...

2. Protons can lead to less side effects in some HNSCC treatments. I do not have randomized data to back it up, but I have seen it in practice.
In well lateralized tumors we were treating (mainly adenoid cystic carcinomas of salivary glands) you would notice very little mucositis.
Although the ipsilateral parts of the oral cavity / tongue were receiving dose during RT, there was a very steep dose drop happening at the mid-line and practically no dose getting to the other side of the oral/cavity tongue (which is the whole point of the Bragg peak). With IMRT you would still have 10-20 Gy in parts of the contralateral oral cavity. Interestingly the mucositis near the midline on the treated site was especially limited.

The speculation was that due to the zero dose on the contralateral side, the mucosa was healing faster near the midline through faster growing mucosa on the contralateral side which was "crossing over". It's a bit like where you get a sore in your mouth and it starts healing through healthy tissue growing around the damaged spot and healing the injured part.

This effect seems not to take place during IMRT since these limited doses to the contralateral side are enough to stop proliferation of the mucosa into the damaged parts in the high-dose area.

Do I have data to back this up? Nope. It's merely the observation we made.

 

[Palex80]

Yes, that's correct. Older linacs have been converted to FLASH mode in a preclinical animal setting, but this only works with electrons, and it's done basically by removing the metal layer that converts electrons to x-rays (which, as you point out, is incredibly inefficient). I think that even if the linac had a mode that would give you 1000x more power for free, you still couldn't do FLASH with x-rays because the metal would melt before the treatment is finished.

Ever heard of the Bialystok incident?

https://www-pub.iaea.org/MTCD/publications/PDF/Pub1180_web.pdf

Scary stuff...

 

[evilbooyaa]

2. Protons can lead to less side effects in some HNSCC treatments. I do not have randomized data to back it up, but I have seen it in practice.
In well lateralized tumors we were treating (mainly adenoid cystic carcinomas of salivary glands) you would notice very little mucositis.
Although the ipsilateral parts of the oral cavity / tongue were receiving dose during RT, there was a very steep dose drop happening at the mid-line and practically no dose getting to the other side of the oral/cavity tongue (which is the whole point of the Bragg peak). With IMRT you would still have 10-20 Gy in parts of the contralateral oral cavity. Interestingly the mucositis near the midline on the treated site was especially limited.

The speculation was that due to the zero dose on the contralateral side, the mucosa was healing faster near the midline through faster growing mucosa on the contralateral side which was "crossing over". It's a bit like where you get a sore in your mouth and it starts healing through healthy tissue growing around the damaged spot and healing the injured part.

This effect seems not to take place during IMRT since these limited doses to the contralateral side are enough to stop proliferation of the mucosa into the damaged parts in the high-dose area.

Do I have data to back this up? Nope. It's merely the observation we made.

I'd even take a retrospective chart review comparing protons to IMRT in head and neck as a starter. If someone can prove protons improve clinical toxicity in a frequently treated site (outside of H&N), that is the easiest slam dunk paper into IJROBP ever.

Hell there was a breast one where toxicity was WORSE with protons and that still got published. Valuable data, albeit with a pro-proton spin in the conclusion. Can you imagine the excitement for actually having better clinical outcomes?

If I worked at a proton center I'd have a medical student cranking out one of these chart reviews once a month for every disease site that was treated with protons. I guess I don't get what's that hard about it. That being said, I'd be looking to publish them regardless of the results, which may go against the wishes of the institution.

 

[scarbrtj]

If I worked at a proton center I'd have a medical student cranking out one of these chart reviews once a month for every disease site that was treated with protons.

Kid you not, I know a proton center where they are hiring two FTEs at ~$200K a year to do essentially this.

 

[RickyScott]

Kid you not, I know a proton center where they are hiring two FTEs at ~$200K a year to do essentially this.

entire job depends on publishing pro proton propaganda?
I have seen one abstract on flash in animals and it had around 1/3 better selectivity than conventional dose rate

 

[medgator]

entire job depends on publishing pro proton propaganda?

At least there is no physical presence requirement!

 

[scarbrtj]

entire job depends on publishing pro proton propaganda?
I have seen one abstract on flash in animals and it had around 1/3 better selectivity than conventional dose rate

At least there is no physical presence requirement!

Yes entire job; and no presence requirement because the FTEs* are not MDs, "just" masters or PhD types.

* I should also mention the FTEs are being funded by the private capital components of the proton venture (which many "academic" proton centers today are at least partially private/for-profit) because they see this as the best and quickest path forward for desperately needed legitimization and medical raison d'être.

 

[McConaughey]

Flash! Ah-ah
Savior of the universe
Flash! Ah-ah
It'll save everyone of us
Flash! Ah-ah
It's a miracle
Flash! Ah-ah
King of the impossible
It's for every one of us

Gordon’s alive?! -Prince Vultan

 

[Photoner]

Very promising, but apparently another group has performed experiments using kV X-rays with dose rates about 40 Gy/s, very close to the ones used in flash, and has found no clear evidence for a normal tissue-sparing effect compared to conventional dose rates... Comparative toxicity of synchrotron and conventional radiation therapy based on total and partial body irradiation in a murine model

Perhaps with electrons it works better than with X-rays?
Many conventional linacs can produce electron beams up to 21 MeV or so and could be modified to do flash. Will we see a revival of the electrons in the form of FLASH?

 

[deleted1008290]

LINAC Flash modifications mostly involves cracking amps to the max and putting the mouse almost inside the treatment head.
The initial team tried high dose rate photons too https://www.thegreenjournal.com/article/S0167-8140(18)33454-6/abstract, seems to work so there is a discrepancy there...
Notably FLASH-proton would put Bragg peak in the bunker walls (because otherwise it would put entrance dose in non flash dose rates)
People working on it are no jokers, results were embargoed for a very very long time because doubts were extraordinarily high.

Imagine the future of oncology if even a fraction of this effect is clinically reproducible. Now that the proverbial cat is finally outside the bag, my take is we won't have to wait for too long anymore...

 

[taserlaser]

I just saw a posting from Institut Curie in Paris that is looking to hire a new rad onc to work with the following:

"To further reinforce clinical research in the field of innovative radiation oncology approaches including MiniBeam (protons) and Flash (electrons and protons), we open a position for a new staff member. Colleagues who feel at their best working in a multidisciplinary team, where research and innovation form part of the daily activities, have good communication skills and would like to develop new research initiatives are very much invited to apply! We propose a position where about 50% of the time will be dedicated to research with as main objective to bringing MiniBeam and Flash to the phase of clinical (research) applications. This work will be done as member of a research team in a research-focussed environment where all necessary infrastructure and techniques are available, including the brand-new RadExP research platform. The other about 50% of the appointment is intended for clinical work with focus areas to be defined. "

Please apply to Philip Poortmans prior to Oct 15. Yes, that Poortmans.

Even at my local (not small) academic centre, there is interest from the physicists in Flash. I will agree that people are looking at this seriously, even if it will take some time.

 

[scarbrtj]

I just saw a posting from Institut Curie in Paris that is looking to hire a new rad onc to work with the following:

"To further reinforce clinical research in the field of innovative radiation oncology approaches including MiniBeam (protons) and Flash (electrons and protons), we open a position for a new staff member. Colleagues who feel at their best working in a multidisciplinary team, where research and innovation form part of the daily activities, have good communication skills and would like to develop new research initiatives are very much invited to apply! We propose a position where about 50% of the time will be dedicated to research with as main objective to bringing MiniBeam and Flash to the phase of clinical (research) applications. This work will be done as member of a research team in a research-focussed environment where all necessary infrastructure and techniques are available, including the brand-new RadExP research platform. The other about 50% of the appointment is intended for clinical work with focus areas to be defined. "

Please apply to Philip Poortmans prior to Oct 15. Yes, that Poortmans.

Even at my local (not small) academic centre, there is interest from the physicists in Flash. I will agree that people are looking at this seriously, even if it will take some time.

LINAC Flash modifications mostly involves cracking amps to the max and putting the mouse almost inside the treatment head.
The initial team tried high dose rate photons too https://www.thegreenjournal.com/article/S0167-8140(18)33454-6/abstract, seems to work so there is a discrepancy there...
Notably FLASH-proton would put Bragg peak in the bunker walls (because otherwise it would put entrance dose in non flash dose rates)
People working on it are no jokers, results were embargoed for a very very long time because doubts were extraordinarily high.

Imagine the future of oncology if even a fraction of this effect is clinically reproducible. Now that the proverbial cat is finally outside the bag, my take is we won't have to wait for too long anymore...

Cool posts mentioning a "cat" and a "mouse" and the French. The Aristocats is an underrated Disney gem. But srsly what the heck does it mean to "[put] the mouse almost inside the treatment head." Je ne comprends pas.

 

[radiation]

Cool posts mentioning a "cat" and a "mouse" and the French. The Aristocats is an underrated Disney gem. But srsly what the heck does it mean to "[put] the mouse almost inside the treatment head." Je ne comprends pas.

Experimental Platform for Ultra-high Dose Rate FLASH Irradiation of Small Animals Using a Clinical Linear Accelerator - PubMed

We present an approach for using a clinical LINAC for FLASH irradiation. We obtained dose rates exceeding 200 Gy/s after simple tuning of the LINAC, with excellent dosimetric properties for small animal experiments. This will allow for increased availability of FLASH irradiation to the general...

www.ncbi.nlm.nih.gov

 

[deleted1008290]

Cool posts mentioning a "cat" and a "mouse" and the French. The Aristocats is an underrated Disney gem. But srsly what the heck does it mean to "[put] the mouse almost inside the treatment head." Je ne comprends pas.

Well, not "almost"

And we can laugh about the French as much as we want, but it seems that with dozens of proton centers in the US, nobody ever had the idea of putting any normal tissues into a full power beam... (or unbelievably, to irradiate some by synchrotron radiation, with hundreds of research teams often working 24/7 on biology problems...damn, even a university prank of blasting a lab rat with any pulsed beam and seeing it NOT die would have rung some bells!)

Half of the FLASH effect was discovered 50 years ago, then got lost.
Only an amazing stroke of serendipity brought it back (if proven to really exist).

Imagine if all was needed was to turn the "Amp" knob, that has been there all along, clockwise? That sort of things are not supposed to happen, still we're starting to smell smoke...

Varian Forms FlashForward Consortium to Study Ultra-high Dose Rate Cancer Treatments with Protons

To expand the encouraging preclinical and translational research already conducted by Varian (NYSE: VAR) and two of its clinical partners, Maryland Proton Treatment Center and Cincinnati...

www.varian.com

Rumors Mevion is on it too

 

[scarbrtj]

Whole Radiotherapy & Oncology issue devoted to FLASH

 

[BobbyHeenan]

Summary: Just turn your Linac up to 11.