Treatment modality question

[SupergreenMnM]

Advertisement - Members don't see this ad

So, I have what may be a dumb question, but since I'm not in the field yet I don't exactly know what I'm missing.

My question is why isn't boron attempted as a treatment (or is it?) used with thermal neutrons? Everything I've read seems to say it would work wells as it can be conjugated to drugs that "somewhat" specifically target a tumor (i.e. like targeting to rapidly dividing endothelial cells). Since from what I've heard there isnt anything out there that targets tumor cells specifically enough to conjugate an alkylating agent to it or an alpha emitter, why not use boron, and then only expose to neutrons the part of the body the tumor is in so you don't need to worry about the nonspecific binding to other parts of the body? Wouldn't that be a doable thing for say head and neck cancer where the depth issue with thermal neutrons wouldn't matter? I've read some stuff from Dr. Eric Hall (@ Columbia) about how boron has a lot of promise but can't seem to see why its not used?

 

[3dtp]

So, I have what may be a dumb question, but since I'm not in the field yet I don't exactly know what I'm missing.

My question is why isn't boron attempted as a treatment (or is it?) used with thermal neutrons? Everything I've read seems to say it would work wells as it can be conjugated to drugs that "somewhat" specifically target a tumor (i.e. like targeting to rapidly dividing endothelial cells). Since from what I've heard there isnt anything out there that targets tumor cells specifically enough to conjugate an alkylating agent to it or an alpha emitter, why not use boron, and then only expose to neutrons the part of the body the tumor is in so you don't need to worry about the nonspecific binding to other parts of the body? Wouldn't that be a doable thing for say head and neck cancer where the depth issue with thermal neutrons wouldn't matter? I've read some stuff from Dr. Eric Hall (@ Columbia) about how boron has a lot of promise but can't seem to see why its not used?

It is not a dumb question at all. In fact it is an excellent question and one that has kept a generation of researchers in business.

Boron-10 was used extensively in tumor doping studies both in the US and in Japan. My dissertation was on BNCT (Boron neutron capture) and Cf-252 dosimetry. Californium-252 is a fissile neutron emitter that emits a thermal neutron spectrum along with photons. While the dosimetry looks very good, and a significant therapeutic advantage in theory can be demonstrated mathmatically and microdosimetrically, there is a fundamental problem. How do you get the B-10 to go where it's supposed to go. When I first started the research, I asked my advisors about this specific issue and the blank stares on their faces sort of told the story. The real issue comes from a couple of perspectives.
1. All atomic species have different neutron interaction cross section probability. This cross section varies with the neutron energy. Thermal or epithermal or even fast neutrons will moderate and change the dosimetry. As a practical matter this is not a huge deal as B-10 for the most part has a huge interaction cross section for np reactions, between around 100-1000 barns depending on the incident neutron energy.

2. The real issue is biological: Where do we need neutrons the most and where do we need them to stay away from? The answer to this is in hypoxic tumors where photons (and other low LET particles) don't work very well. So, by taking your observation that Boron is a covalent atom which can be bound to drug bases and thus transported to the tumor, we find that chronically hypoxic cells are either not actively metabolizing, (ie dormant) or are nutrient deprived because of poor vascularization in the core. This limits the [B-10] available in hypoxic cells. The [B-10] in non-hypoxic cells will also be taken up by tumor and normal tissue thus depriving the tumor of the therapeutic window in excess of that already available. The Detroit Cyclotron attempted to overcome this by rebuilding their collimation system to take advantage of the MLC and IMRT technology, but it is my understanding that this machine is being closed soon, if it hasn't already, before they really had a chance to investigate the full potential of the machine.

This is unfortunate since I think that we have missed the boat with neutron therapy and I have some ideas of my own I'd like to try with neutron radiosensitization agents. I'm not willing to live in Freiburg or Geneva for as long as it would take to conduct this study. That leaves only the Seattle Group with an operating clinical cyclotron in the US. Perhaps someday we can revisit this. Come to think of it, I wouldn't mind living in Seattle to try out the project.....

Also, protons, while they have the advantage of highly precise dosimetry are not substitutes for neutrons. They are for all intents and purposes, low LET particles, delivering the bulk of their energy at the end of their track length.

An additional problem exists with neutrons in head and neck cases. Neutrons given at therapeutic doses can cause conversion and subsequent radioactivation of isotopes used in the dental work and in prosthesis. Titanium can be activated to isotopes with long enough half lives to give a significant photon dose on top of the neutron dose, and not necessarily where you want additional dose. The dosimetry becomes a tad more interesting, but not insurmountable.

I'm all in favor of neutrons and I think we have more knowledge of how they work, why they work and there's been enough work done by the group in Detroit that has demonstrated the usefulness in prostate cancer and refractory lymphomas. We know the toxicity issues and have some ideas on how to avoid that toxicity. It remains to be seen how the hypofractionated prostate protocols will pan out in the long run and whether the late effects will make them a fully viable treatment comparable to the neutron results without BNCT.

So, when you get ready, you want to help me find a cyclotron we can use to make a reasonable neutron beam and try some stuff out?

 

[stephew]

the delivery of this modality is difficult an there were some deaths a couple odf decades ago that have put a hamper on things. ,

 

[3dtp]

the delivery of this modality is difficult an there were some deaths a couple odf decades ago that have put a hamper on things. ,

This is true, but those deaths were well before we understood the biology of high LET radiation. At the time, the doses used were the same as photon doses, ie if the standard photon dose was 45 Gy, the neutron dose used was 45 neutron-Gy. They are biologically not equivalent.

With neutrons, initially we did not understand the RBE and quality factors. Neutron irradiaiton has dose multiplier between 3 and 8 times that of an equivalent photon dose. We understand the underlying biology and physics much better. Yoshi Maruyama did work on this when he was at UKy. In initial treatments, he used a 1:1 equivalency neutron dose to photon dose. This caused substantial morbidity and mortality. Forman in Detroit used an RBE of 3-4 in his prostate cancer series and probably has the most published experience with prostate and neutrons. He uses 10 NGy in 10 fractions delivered as a 6 field highly conformal treatment to the prostate/SV followed by 45 Gy photons in more conventional 1.8Gy/fraction. With that dose scheme, he estimates an equivalent total photon dose of 10 NGy x 3 hvGy/NGy=30 hvGy + 45 Gy = 75 Gy-equiv. If the RBE factor is actually 4, the Hammerschmidt group's estimates, then the equivalent photon dose is 85 Gy.

Maruyama and earlier pioneers used 30-40 Neutron Gray without realizing the photon equivalent dose was, in reality 30x (3-5) to 40 x(3-5) or doses in the rante of 90-150 photon Gray equivalent. And with neutrons, there is minimal to no repair resulting in very high morbidity and mortality. Forman, on the other hand with his dosing scheme has reported comparable morbidity to more conventional (and safer) photon doses. The Hutchinson center has likewise demonstrated comparable dose toxicity and both groups have reported better local-regional control of high risk prostate cancer (GS >7, PSA > 20) than with photons alone.

Boron neutron capture does not change this picture appreciably, except that when it captures an neutron, it emits an energetic proton and deposits that energy very locally to the point where the capture event took place. In theory, this could give us a therapeutic advantage, except the boron goes to well oxygenated cells and only increases the toxicity. I think there are better ways to do this, but neutrons are getting very hard to come by, these days and beam ports off of reactors is not an ideal irriadiator. I have heard rumors that Argonne may restart their neutrons, but these are but rumors.

'tis a pity in my opinion, we will not be able to fully explore the potential.

 

[SupergreenMnM]

Wow, thank you for the replies. I'm pretty interested in the topic and since I'm new I'm probably naturally drawn to interesting things that other people aren't using. It seems the field is moving towards proton and carbon-12 therapy and I agree it seems a shame that neutron therapy is not being explored. As to the question at the end of your first post, yes, if you don't mind waiting 5 years 🙂

 

[stephew]

sure they had an idea. other wise why use it? but no, they didnt appreciate the issues as much. Frankly im still not convinced you couldnt get the same effect by just upping photon dose and improving dosimetry.there were other issues with that project as well.

This is true, but those deaths were well before we understood the biology of high LET radiation. At the time, the doses used were the same as photon doses, ie if the standard photon dose was 45 Gy, the neutron dose used was 45 neutron-Gy. They are biologically not equivalent.

With neutrons, initially we did not understand the RBE and quality factors. Neutron irradiaiton has dose multiplier between 3 and 8 times that of an equivalent photon dose. We understand the underlying biology and physics much better. Yoshi Maruyama did work on this when he was at UKy. In initial treatments, he used a 1:1 equivalency neutron dose to photon dose. This caused substantial morbidity and mortality. Forman in Detroit used an RBE of 3-4 in his prostate cancer series and probably has the most published experience with prostate and neutrons. He uses 10 NGy in 10 fractions delivered as a 6 field highly conformal treatment to the prostate/SV followed by 45 Gy photons in more conventional 1.8Gy/fraction. With that dose scheme, he estimates an equivalent total photon dose of 10 NGy x 3 hvGy/NGy=30 hvGy + 45 Gy = 75 Gy-equiv. If the RBE factor is actually 4, the Hammerschmidt group's estimates, then the equivalent photon dose is 85 Gy.

Maruyama and earlier pioneers used 30-40 Neutron Gray without realizing the photon equivalent dose was, in reality 30x (3-5) to 40 x(3-5) or doses in the rante of 90-150 photon Gray equivalent. And with neutrons, there is minimal to no repair resulting in very high morbidity and mortality. Forman, on the other hand with his dosing scheme has reported comparable morbidity to more conventional (and safer) photon doses. The Hutchinson center has likewise demonstrated comparable dose toxicity and both groups have reported better local-regional control of high risk prostate cancer (GS >7, PSA > 20) than with photons alone.

Boron neutron capture does not change this picture appreciably, except that when it captures an neutron, it emits an energetic proton and deposits that energy very locally to the point where the capture event took place. In theory, this could give us a therapeutic advantage, except the boron goes to well oxygenated cells and only increases the toxicity. I think there are better ways to do this, but neutrons are getting very hard to come by, these days and beam ports off of reactors is not an ideal irriadiator. I have heard rumors that Argonne may restart their neutrons, but these are but rumors.

'tis a pity in my opinion, we will not be able to fully explore the potential.

 

[3dtp]

sure they had an idea. other wise why use it? but no, they didnt appreciate the issues as much. Frankly im still not convinced you couldnt get the same effect by just upping photon dose and improving dosimetry.there were other issues with that project as well.

You might be able to. Hypofractionation is all the rage right now and with precision targeting, it is likely we will increase the DS breaks and cluster damage rates. But with the current hypofractionation schemes (I'm thinking in particularl about Ritter's hypofractionated prostate protocol,) the new question becomes: Is the ratio of DS:SS breaks important in local tissue repair and if so, will we see serious late effects as we approach 4-5 Gy/fraction doses compared to conventional dosing levels? Even if we include the BED or EQD2 equivalent doses.

My concern with the hypofractionated schemes is that the D0 is fairly well quantified, and we know this dose/fraction gives us a reasonable compromise between toxicity and local control.

I think it would be an exceptional advance if the highly targeted hypofractionated photon schemes work with acceptable toxicity. I will be following the UW protocol very carefully. The study is acruing at a high rate, so we should have some good data in a few years. I'd love to be convinced since this will decrease the cost and time to cure. Photons cost a lot less than neutrons or protons, to be sure, and hypofractionated photons cost even less. Late effects will tell the tale, and those take time to become manifest.

We do not have and likely will not have the same opportunity to get the data with neutrons. Despite the fact that we understand the biology and the same improvements in photon planning and delivery have been made and could be made available with neutrons.

Then the real question is: What exactly do we need to target with our improved dosimetry which will allow decreased NTCP and increased TCP/LRC? That is the real question, now isn't it?

 

[cdf95cro]

3D-
One of our former faculty who was a big neutron researcher in the 80s was mentioning that the big ramp-up in proton facilities may revive neutrons in other places than Seattle, since all you need is a berylium/lithium target.

Apparently, this was a potential selling point for some of the early proton vendors (protons and neutrons from the same unit)....interesting to see how it will develop.

 

[G'ville Nole]

I think it would be an exceptional advance if the highly targeted hypofractionated photon schemes work with acceptable toxicity. I will be following the UW protocol very carefully. The study is acruing at a high rate, so we should have some good data in a few years. I'd love to be convinced since this will decrease the cost and time to cure. Photons cost a lot less than neutrons or protons, to be sure, and hypofractionated photons cost even less. Late effects will tell the tale, and those take time to become manifest.

...warning, slight topic hijacking to follow...

Off protocol, we treat using the Kupelian regimen (70Gy/28fx). Obviously, reproducible immobilization and image guidance is a necessary pre-requisite for any of these hypofractionation schemes. As you point out, good toxicity data for our hypofractionation protocol is a few years away. Without revealing anything I'm not supposed to, I can direct you to last year's ASTRO (abstract 19). GU and GI toxicity in the sub-acute setting is pretty good; I'd fully agree that the jury is out on late effects at this point, though.

The 51.6Gy/12fx (4.35 Gy per fx) level has met accrual goals (50 pts). PM me if you'd like to discuss this further.

 

[G'ville Nole]

3D-
One of our former faculty who was a big neutron researcher in the 80s was mentioning that the big ramp-up in proton facilities may revive neutrons in other places than Seattle, since all you need is a berylium/lithium target.

Or just a collimator! 🙂 🙂

 

[3dtp]

...warning, slight topic hijacking to follow...

Off protocol, we treat using the Kupelian regimen (70Gy/28fx). Obviously, reproducible immobilization and image guidance is a necessary pre-requisite for any of these hypofractionation schemes. As you point out, good toxicity data for our hypofractionation protocol is a few years away. Without revealing anything I'm not supposed to, I can direct you to last year's ASTRO (abstract 19). GU and GI toxicity in the sub-acute setting is pretty good; I'd fully agree that the jury is out on late effects at this point, though.

The 51.6Gy/12fx (4.35 Gy per fx) level has met accrual goals (50 pts). PM me if you'd like to discuss this further.

Not a hijacking at all. This is similar to what we've seen on the Wisconsin protocol. We're treating at Level II 3.63 x 16 fractions. Targetting is, indeed, everything. Very little acute toxicities. We're seeing the same in precisely targeted peripheral lung tumors. Good early response, few to zero early toxicities. We've given up to 6.2 Gy/fx but the average is around 2.8 Gy/fx in patients with otherwise good lung and PFT numbers. I have a year to see how these patients turn out, so it'll be interesting to watch.

Of neutrons and collimations: This is the rub with the protons. It's pretty easy to make neutrons with the cyclotrons being used to make protons, in theory. But there are a number of obstacles. I have been discussing this with one center being built about the feasibility of making a beam port off the main gantry and construction of a Be target. But that is exactly the way to make neutrons.

 

[stephew]

you know you can always tell where someone is training by what they think is "all the rage". its something you see more in radonc than any other field i think; there is such diversity in practice and protocol and training varies rather widely, place to place, moreso than in other fields.

 

[radonc]

who is talking about 'all the rage'. those posters just mentioned what they do at their institution. it seems as if 'all the rage' is treating patients on protocol. and actually i would argue that other fields are more apt to treat patients by 'all the rage' techniques/modalities/medicines OFF PROTOCOL than are radiation oncologists.

 

[G'ville Nole]

you know you can always tell where someone is training by what they think is "all the rage". its something you see more in radonc than any other field i think; there is such diversity in practice and protocol and training varies rather widely, place to place, moreso than in other fields.

You can tell where I'm training by checking out the "location" under my handle. For that matter, you can probably deduce where I went to med school and undergrad🙂 .

Steph, I took your post as more observation than pejorative. To be clear, I don't hold hypofx for prostate ca to be "all the rage", if that's what you're alluding to. I'm guardedly optimistic that it may represent a good treatment alternative which is a) potentially more convenient for patients, with fewer trips to the clinic, and b) backed by fundamentally sound radiobiology (although there is sure to be continued arm wrestling in this arena).

Early stage prostate ca is one of those areas where demonstrating superiority of one technique over the other will continue to be exceedingly difficult; probably the best that can be hoped for is demonstrable non-inferiority with no additive toxicity. I'll reiterate that practices which have not devoted resources to immobilization and image guidance techniques should not be routinely doing hypofx. When I land in a practice, I'll have no qualms about giving 2Gy x 38, especially if the above criteria haven't been met.

But I'll probably do it with tomotherapy (damn, training bias creeping in again!)

 

[stephew]

there was a good imrt conference in st petersburg recently that did a lovely job at compaing the various modalities on many dimensions. the vendors we're well reigned in. those who attended it faithfully throughout learned a lot about the physics involved in treatment, and were forced to see beyond their own departmental bias. the bottom line is that there is no one "best" technology. it was quite interesting.

btw the use of boron neutron capture is VERY complex in terms of the delievery. even if it was more available, its not easy to do.

 

[3dtp]

there was a good imrt conference in st petersburg recently that did a lovely job at compaing the various modalities on many dimensions. the vendors we're well reigned in. those who attended it faithfully throughout learned a lot about the physics involved in treatment, and were forced to see beyond their own departmental bias. the bottom line is that there is no one "best" technology. it was quite interesting.

btw the use of boron neutron capture is VERY complex in terms of the delievery. even if it was more available, its not easy to do.

Yes. That's why it was dissertation fodder and I came to the conclusion long before I got to that point that it would never work. But, quoting Yoda, "...there is another...sky...walker..."

 

[ParticlePower]

who is talking about 'all the rage'. those posters just mentioned what they do at their institution. it seems as if 'all the rage' is treating patients on protocol. and actually i would argue that other fields are more apt to treat patients by 'all the rage' techniques/modalities/medicines OFF PROTOCOL than are radiation oncologists.

I agree. Radiation Oncology is one of the most, and maybe the original, evidence based field in medicine. However, machines an institution has at their disposal, OR what they have recently invested large sums of money in, does tend to dictate what they think is all the rage. For example, treating prostate cancer patient with proton therapy only makes sense financially. That is, attempting to keep the numbers of patients on treatment high enough to make proton therapy profitable after a huge capital investment. I'm hoping these practices will change when more refined proton facilities (or other better modalities) that cost less than $100 million+ make their way into mainstream within the next 5-8 years.

 

[BigAppleOnc]

So, I have what may be a dumb question, but since I'm not in the field yet I don't exactly know what I'm missing.

My question is why isn't boron attempted as a treatment (or is it?) used with thermal neutrons? Everything I've read seems to say it would work wells as it can be conjugated to drugs that "somewhat" specifically target a tumor (i.e. like targeting to rapidly dividing endothelial cells). Since from what I've heard there isnt anything out there that targets tumor cells specifically enough to conjugate an alkylating agent to it or an alpha emitter, why not use boron, and then only expose to neutrons the part of the body the tumor is in so you don't need to worry about the nonspecific binding to other parts of the body? Wouldn't that be a doable thing for say head and neck cancer where the depth issue with thermal neutrons wouldn't matter? I've read some stuff from Dr. Eric Hall (@ Columbia) about how boron has a lot of promise but can't seem to see why its not used?

Great question! Look for more work done along these lines, and a general acceleration of this field of study, in the next ten years.

 

[stephew]

far less likely than more work on other particles.

 

[cdf95cro]

I agree w Steph...protons and neutrons are going to be pwned by anti-matter radiotherapy!! (JK)



http://press.web.cern.ch/Press/PressReleases/Releases2006/PR15.06E.html