oxygen in XRT

[ABCXRT]

I've seen several studies showing improved results with hyperbaric oxygen (HBO) or other oxygen delivery, especially in cervical cancer and head and neck cancer. Hall even sets aside an entire chapter for the benefits of oxygen.

Why is tumor oxygenation not used in current practice? Is it just that HBO is cumbersome, or is it thought fractionation is sufficient for reoxygenation? How about for brachy and radiosurgery where the doses are fewer and larger?

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[radiaterMike]

I may be mistaken but I am under the impression that hypoxic RT sensitizers have not added much benefit, at least not compared to the addition of chemotherapy. You are correct that there are some studies that show a benefit, although most studies have not. Hyperbaric oxygen chambers are used for wound healing, RT necrosis, etc. The logistics of using one of these in the same room as a LINAC is complex and costly.

The mechanism of cell damage from SRS may be able to overcome hypoxia (there was a recent editoral in the Red J about this from the Stanford group).

 

[IndyXRT]

I may be mistaken but I am under the impression that hypoxic RT sensitizers have not added much benefit, at least not compared to the addition of chemotherapy. You are correct that there are some studies that show a benefit, although most studies have not. Hyperbaric oxygen chambers are used for wound healing, RT necrosis, etc. The logistics of using one of these in the same room as a LINAC is complex and costly.

The mechanism of cell damage from SRS may be able to overcome hypoxia (there was a recent editoral in the Red J about this from the Stanford group).

Yes - the benefit is only seen if you essentially are in the HBO chamber under pressure when you receive the RT (at least that's how I remember it from radbio class; someone correct me if I'm wrong). I can't remember who, but I remember someone describing putting a linac in an HBO chamber as analagous to creating a giant bomb in your clinic.

 

[radonc]

I've seen several studies showing improved results with hyperbaric oxygen (HBO) or other oxygen delivery, especially in cervical cancer and head and neck cancer. Hall even sets aside an entire chapter for the benefits of oxygen.

Why is tumor oxygenation not used in current practice? Is it just that HBO is cumbersome, or is it thought fractionation is sufficient for reoxygenation? How about for brachy and radiosurgery where the doses are fewer and larger?

for hdr brachy and radiosurgery, the large dose per fraction is able to overcome any benefit that oxygen is able to provide with respect to dna damage as compared to the therapeutic ratio when using normal fractionation schemes.

tumor oxygenation is gaining a renewed interest in imaging circles as hypoxic imaging is taking off (penn, mskcc, uw). using imrt, one may be able to dose-paint based on hypoxic pet imaging; ie giving a higher dose per fraction to hypoxic areas while giving normal dose per fraction to non-hypoxic areas. assessment of hypoxia is still experimental and so is treating patients based on hypoxic imaging.

use of hyperbaric oxygen chambers is tedious; not many centers have them; im unsure about the cost issue; not too much hype in north america about this topic.

 

[clintpark]

Yes - the benefit is only seen if you essentially are in the HBO chamber under pressure when you receive the RT (at least that's how I remember it from radbio class; someone correct me if I'm wrong). I can't remember who, but I remember someone describing putting a linac in an HBO chamber as analagous to creating a giant bomb in your clinic.

Just noticed IndyXRT is now an attending. Congrats!

 

[ABCXRT]

for hdr brachy and radiosurgery, the large dose per fraction is able to overcome any benefit that oxygen is able to provide with respect to dna damage as compared to the therapeutic ratio when using normal fractionation schemes.

From the chapter in Hall it looks like a hypoxia would actually be a bigger factor with a large dose. Of course more cells die with a higher dose, but the oxic and hypoxic curves really separate out as the dose goes up.

I really couldn't find much clinical data or animal studies on oxygen and radiosurgery or HDR. Is there a paper I could read that shows it is not a factor?

Thank you all for your replies!

 

[radiaterMike]

I believe the figure in Hall is from cells in tissue culture, comparing oxic to hypoxic conditions. With tumors, the issue still remains as to how to get oxygen to the hypoxic regions. These regions already have compromised blood flow (which can be a transient effect), and thus the "extra" oxygen from HBO (which arguably is not that much) may not be all that effective. Hypoxic RT sensitizers are more readily absorbed and/or effective in hypoxic regions. They can penetrate microscopic hypoxic regions. Grossly necrotic regions with compromised blood flow may not benefit much from these either.

SRS/SBRT may cause damage through other mechanisms (which are not fully understood- i.e. damaging tumor vasculature, immune response, etc. These mechanisms may overcome hypoxia.

check out: http://www.ncbi.nlm.nih.gov/pubmed/18474308

From the chapter in Hall it looks like a hypoxia would actually be a bigger factor with a large dose. Of course more cells die with a higher dose, but the oxic and hypoxic curves really separate out as the dose goes up.

I really couldn't find much clinical data or animal studies on oxygen and radiosurgery or HDR. Is there a paper I could read that shows it is not a factor?

Thank you all for your replies!

 

[ABCXRT]

SRS/SBRT may cause damage through other mechanisms (which are not fully understood- i.e. damaging tumor vasculature, immune response, etc. These mechanisms may overcome hypoxia.

check out: http://www.ncbi.nlm.nih.gov/pubmed/18474308

I did have a chance to look at that article commenting on the results of the Fuks paper. I've never heard him speak, but from his papers it seems like Fuks has been advocating an alternative vascular damage pathway for a while. If true (and as you point out, the jury is definitely still out), this may be an additional mechanism for cell death.

Unless this potential new mechanism is the only way cells are killed, it still seems to me that hypoxia would still contribute to resistance at high doses of radiation. Radonc, is this paper the main reason you say that high dose radiation overcomes any benefit of oxygen, or are there others?

You've all answered my main question though. We don't use HBO because it's too difficult and the oxygen may not get everywhere it's need anyway. Hypoxia targeting agents may be easier to deliver and get to the hypoxic cells, but they haven't given good enough clinical results. Thank you!

 

[radonc]

Unless this potential new mechanism is the only way cells are killed, it still seems to me that hypoxia would still contribute to resistance at high doses of radiation. Radonc, is this paper the main reason you say that high dose radiation overcomes any benefit of oxygen, or are there others?

oxygen is a always a good thing, the more you have, the more it enhances radiation induced damage. you are correct about that. what i meant to depict was that at higher doses per fraction, under 'standard in vivo' oxygenation conditions, one is able to cause more double strand breaks via the direct pathway in hypoxic cells than with traditional fractionation schemes.

 

[Easterly]

I believe the Danish (the guys behind the DAHANCA study) use nimorazole, and they've proven it works for loc adv head and neck. HBO chambers, as has been written, are really inconvenient to have within the vault. Carbogen or ARCON breathing, however, is a way to solve hypoxia. The setup looks a little bulky but not bad. I'm not sure why it's not more widely used. I've heard that if you use 98% O2 and 2% CO2 (carbogen-light) that it's actually quite tolerable. The nicotinamide gives you a sensation of asphyxiation. This is from Dr Joiner's (Wayne State) talk on hypoxia at the Maryland Bio Refresher.

 

[stephew]

there is more theory than understanding about this topic. People dont understand a lot of about radiobio including necrosis and BED. In fact im always astounded when I read published papers that give BED equivs for radiosurgery. That formula (which is useful but imperfect) completely falls apart at higher doses and is useless in the SRS range.

 

[trublu]

I believe the Danish (the guys behind the DAHANCA study) use nimorazole, and they've proven it works for loc adv head and neck. HBO chambers, as has been written, are really inconvenient to have within the vault. Carbogen or ARCON breathing, however, is a way to solve hypoxia. The setup looks a little bulky but not bad. I'm not sure why it's not more widely used. I've heard that if you use 98% O2 and 2% CO2 (carbogen-light) that it's actually quite tolerable. The nicotinamide gives you a sensation of asphyxiation. This is from Dr Joiner's (Wayne State) talk on hypoxia at the Maryland Bio Refresher.

Jens Overgaard gave a great talk at AHNS last month essentially imploring the (largely American) audience to reconsider oxygen modification as a viable, cheaper, and less-toxic alternative to concurrent chemo or targeted therapies for locally advanced HNSCC. He probably won no converts, but it was a very interesting talk.

 

[scarbrtj]

That formula (which is useful but imperfect) completely falls apart at higher doses

Tardy to the party, but I'm not sure why people constantly say this like it's settled science. There is no data to support it "completely" falling apart; in fact, the data show the opposite: ie, the curve (and formula) match predicted vs. measured BED on up to 20 Gy.