SBRT Bone Met Question

[sirspamalot]

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Fractionated brain mets lol. Unless they are sitting next to the optic chiasm or some other good reason (yeah, you can name a few more) why on earth would anyone do it unless they just need to keep the department humming along - does it pay better vs single fraction?

I know you're gonna say it so I'll see myself out: see Rule 1 as to Why Questions.

 

[TheWallnerus]

I meant 10 Gy x 5 and I agree with your reasoning.

But I also don't think applying an a/b for very hypofractionated regimens is something that one should have a lot of confidence in. There are lots of reasonable regimens that work, and in my opinion, the slightly less hypofractionated ones tend to have a better side effect profile (lower incidence of things like symptomatic brain necrosis or vertebral body collapse).

Don’t mean to beat this horse to death but since “alpha/beta” (and LQ and a BED-Gy-x) will in general tend to predict/verify your clinical hypotheses, why not have confidence in it? (And specifically you’re talking about “late responding tissues,” something that makes sense given LQ but doesn’t afaik without it.) All the in vitro cell survival studies looked at fractional doses well up to and past 10 Gy. There was never any hint, that I’ve seen, of the model itself breaking down as the fraction sizes got higher well past 3 Gy.

 

[Ray D. Ayshun]

Fractionated brain mets lol. Unless they are sitting next to the optic chiasm or some other good reason (yeah, you can name a few more) why on earth would anyone do it unless they just need to keep the department humming along - does it pay better vs single fraction?

I know you're gonna say it so I'll see myself out: see Rule 1 as to Why Questions.

Single-Fraction Versus Multifraction (3 × 9 Gy) Stereotactic Radiosurgery for Large (>2 cm) Brain Metastases: A Comparative Analysis of Local Control and Risk of Radiation-Induced Brain Necrosis - PubMed

Multifraction SRS at a dose of 27 Gy in 3 daily fractions seems to be an effective treatment modality for large brain metastases, associated with better local control and a reduced risk of radiation-induced radionecrosis as compared with SF-SRS.

pubmed.ncbi.nlm.nih.gov

Id give myself 3

 

[OTN]

Fractionated brain mets lol. Unless they are sitting next to the optic chiasm or some other good reason (yeah, you can name a few more) why on earth would anyone do it unless they just need to keep the department humming along - does it pay better vs single fraction?

I know you're gonna say it so I'll see myself out: see Rule 1 as to Why Questions.

Data is clear (one example posted just above) that fractionated radiosurgery helps with both local control and chance of radionecrosis for larger lesions- my cutoff is 2 cm.

 

[Ray D. Ayshun]

Well, tbh, id give myself 3 because I have good insurance.

 

[sirspamalot]

A. Yes, for large* lesions, one follows RTOG and sure enough, lower BED to reduce risk = lower biological effectiveness.
B. For smaller lesions, there is no doubt single fraction is satisfactory. Background snip: For example, the volume of brain tissue receiving 12 Gy or more in radiosurgery appears to be correlated with the risk of radionecrosis, particularly when this volume exceeds 10–15 mL. Note, however, that this limitation appears overly restrictive, as it appears that virtually every single-fraction radiosurgery plan would exceed this limit when large lesions were treated to accepted doses.2

Thus, the only remaining question is: what is the cutoff for symptomatic necrosis (volume/dimension) where fractionation becomes a winner? Do I hear 3 cm? 4 cm? 5 cm?

ps. some patients are struggling to make it thru one fraction. for those folks, one it is based on life expectancy.

 

[taserlaser]

A. Yes, for large* lesions, one follows RTOG and sure enough, lower BED to reduce risk = lower biological effectiveness.
B. For smaller lesions, there is no doubt single fraction is satisfactory. Background snip: For example, the volume of brain tissue receiving 12 Gy or more in radiosurgery appears to be correlated with the risk of radionecrosis, particularly when this volume exceeds 10–15 mL. Note, however, that this limitation appears overly restrictive, as it appears that virtually every single-fraction radiosurgery plan would exceed this limit when large lesions were treated to accepted doses.2

View attachment 363045

Thus, the only remaining question is: what is the cutoff for symptomatic necrosis (volume/dimension) where fractionation becomes a winner? Do I hear 3 cm? 4 cm? 5 cm?

ps. some patients are struggling to make it thru one fraction. for those folks, one it is based on life expectancy.

Similarly, there is data for T1 non-melanoma skin cancer where there is good local control with single fr ~20 Gy x 1, but past that point risk of skin necrosis increases. Digging down into the references and results prior radiobiological experiments decades past, iirc there was not any benefit to fractionation for local seen until lesions were >2cm.

 

[communitydoc13]

what is the cutoff for symptomatic necrosis (volume/dimension)

These things are not binary. The cutoff for any side effect is highly variable and patient dependent. So to me the following questions should be asked in order.

1. What is safe (meaning is it below the threshold for causing badness even for the 5% most sensitive people)
2. What is effective
3. What is convenient

IMO going from 1-->3 fractions in many sites is minimally more inconvenient, equally effective, and is almost always safer (although marginally as we approach some limit).

Don’t mean to beat this horse to death but since “alpha/beta” (and LQ and a BED-Gy-x) will in general tend to predict/verify your clinical hypotheses, why not have confidence in it?

I know we've talked about this before. It's math to me. LQ is a 2nd order polynomial function fit to data that is what it is (the data would be even better approximated by a 3rd or 4th order polynomial or many types of infinite series). The fit is always best within a certain domain (fraction size). In addition, at some point in many bio systems weird things happen with curves that are unexpected and not even monotonic.

 

[TheWallnerus]

Similarly, there is data for T1 non-melanoma skin cancer where there is good local control with single fr ~20 Gy x 1, but past that point risk of skin necrosis increases. Digging down into the references and results prior radiobiological experiments decades past, iirc there was not any benefit to fractionation for local seen until lesions were >2cm.

This is a fascinating and terribly interesting discussion to me. Prostate people were trying "virtual prostatectomies" with single fraction EBRT approaches. I think single fraction "can" (serious air quotes) always work, at least oncologically. (Spillover of the dose into normal tissues is another discussion obv.) But when you get up into high fraction sizes and tumor alpha/betas that are near or below normal tissue alpha/beta, you get EXTREME fractional (fraction size) sensitivity. And by that the best analogy I can think of is like with hypercars... and that above 200mph it takes an extra 8hp for every extra 1mph you try and go faster. There may not seem that much difference, mathematically, between 20 Gy and 22 Gy e.g. But in certain "LQ situations" that difference can be very CLINICALLY noticeable both in terms of LC and toxicity.

 

[RadOncDoc21]

Are we now fraction shaming over 1-2 fractions now? Rad oncs, I tell ya… always trying to prove how smart we are. Meanwhile ortho docs are pretending they can’t read.

 

[evilbooyaa]

Regarding the asymptote, not necessarily imho (again will depend on Tpots, alpha/betas, etc).

E.g. say a tumor has a D-zero of 2 Gy (sort of radiosensitive). Treating a billion cell tumor mass (and that may be overestimate for small-ish targets...but anyways)...

10Gy x 5 = ((0.37^5)^5)*1E9 = 0.016 = 98.4% LC probability
18Gy x 3 = ((0.37^9)^3)*1E9 = 0.002 = 99.8% LC probability

IRL, it would seem like "both work" the same (and they essentially would, for a D-zero equals 2 Gy tumor), no significant "asymptotic flirtation" w/ the 50Gy/5fx. The D-zero of some head/neck cancers is probably close to 2 Gy; the D-zero of prostate cancer is certainly more than 2 Gy.

You have a very reasonable Radiobiological answer accepting some assumptions.

What I am referencing are clinical answers suggesting that BED < 100 portends for significantly lower local control in NSCLC. Yes, similar thresholds have been suggested for 110, or 140, or whatever other BED, but still pretty solid tumor control with 50/5 (no different than 60/5 which we know is higher BED), while at lower BEDs it seems to be lower, in NSCLC. The 'threshold' is likely different for different tumors in part based on their a/b (see liver metastases from CRC), but just focusing on one disease site.

I meant 10 Gy x 5 and I agree with your reasoning.

But I also don't think applying an a/b for very hypofractionated regimens is something that one should have a lot of confidence in. There are lots of reasonable regimens that work, and in my opinion, the slightly less hypofractionated ones tend to have a better side effect profile (lower incidence of things like symptomatic brain necrosis or vertebral body collapse).

Think 9Gy x 3, 12 Gy x 2 or 18Gy x 1 for spine mets or fractionated SBRT regimens for brain mets.

Agreed, but they are all pretty similar when it boils down with the linear quadratic formula and a/b. I agree that with single fraction some aspects of linear quadratic aren't great, but I do feel relatively comfortable getting at least in the ballpark for say 3 or especially 5 fractions.

Those who have 'knocked' linear quadratic have not proposed anything really 'better' IMO.

 

[evilbooyaa]

Fractionated brain mets lol. Unless they are sitting next to the optic chiasm or some other good reason (yeah, you can name a few more) why on earth would anyone do it unless they just need to keep the department humming along - does it pay better vs single fraction?

I know you're gonna say it so I'll see myself out: see Rule 1 as to Why Questions.

It's probably not the 'majority of SRS treatments' but fractionated SRT should be a pretty solid staple of most folks's practice... Can't meet V12 < 5-10cc for single fraction? Do 9Gy x 3. Just as effective and will lower rate of necrosis. Can meet it? Then just do single fraction. Similar thought process for going from 3 to 5 fractions, just different numbers.

Showing your age with this reply.

 

[TheWallnerus]

What I am referencing are clinical answers suggesting that BED < 100 portends for significantly lower local control in NSCLC. Yes, similar thresholds have been suggested for 110, or 140, or whatever other BED, but still pretty solid tumor control with 50/5 (no different than 60/5 which we know is higher BED), while at lower BEDs it seems to be lower, in NSCLC

That 50/5 seems to work as well as things that are higher BED implies many interesting things, no matter the disease site. First it may imply that we are overestimating clonogen number within the apparent radiographic GTV (there is evidence eg that CT very over estimates the tumor edge extent in NSCLC, that a billion cancer cells per cc is wrong, etc). Second it may imply, for NSCLC eg, that we are dealing with slower growing and thus more late responding (and lower alpha/beta… a lot lower than 10) NSCLC cells than we might otherwise suspect; there is data for this too. Third, it may imply a mysterious radiobiology. I favor the latter implication the least!

 

[sirspamalot]

Showing your age with this reply

Showing your lack of class with this reply. No need to get ugly.

 

[evilbooyaa]

Showing your lack of class with this reply. No need to get ugly.

 

[A_DeMichele]

The age of a doctor can influence their medical decision making. Younger doctors may be more likely to embrace new technologies and treatments, while older doctors may rely on their experience and established methods. Additionally, older doctors may have more experience and therefore be better able to accurately diagnose and treat patients. However, it is important for doctors of all ages to stay up-to-date on the latest medical research and treatments in order to provide the best care for their patients.

 

[RadOncDoc21]

The age of a doctor can influence their medical decision making. Younger doctors may be more likely to embrace new technologies and treatments, while older doctors may rely on their experience and established methods. Additionally, older doctors may have more experience and therefore be better able to accurately diagnose and treat patients. However, it is important for doctors of all ages to stay up-to-date on the latest medical research and treatments in order to provide the best care for their patients.

I’m reporting you, this kind of post does not belong here!

 

[radiation]

Don’t mean to beat this horse to death but since “alpha/beta” (and LQ and a BED-Gy-x) will in general tend to predict/verify your clinical hypotheses, why not have confidence in it? (And specifically you’re talking about “late responding tissues,” something that makes sense given LQ but doesn’t afaik without it.) All the in vitro cell survival studies looked at fractional doses well up to and past 10 Gy. There was never any hint, that I’ve seen, of the model itself breaking down as the fraction sizes got higher well past 3 Gy.

Lots of papers challenging accuracy of LQ model for higher doses

The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery - PubMed

The linear-quadratic (LQ) model is widely used to model the effect of total dose and dose per fraction in conventionally fractionated radiotherapy. Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery. Clinically, the LQ model often...

pubmed.ncbi.nlm.nih.gov

Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy - PubMed

The USC can be used to compare the dose fractionation schemes of both CFRT and SBRT. The USC provides an empirically and a clinically well-justified rationale for SBRT while preserving the strengths of the LQ model for CFRT.

pubmed.ncbi.nlm.nih.gov

 

[sirspamalot]

 

[TheWallnerus]

Lots of papers challenging accuracy of LQ model for higher doses

The linear-quadratic model is inappropriate to model high dose per fraction effects in radiosurgery - PubMed

The linear-quadratic (LQ) model is widely used to model the effect of total dose and dose per fraction in conventionally fractionated radiotherapy. Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery. Clinically, the LQ model often...

pubmed.ncbi.nlm.nih.gov

Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy - PubMed

The USC can be used to compare the dose fractionation schemes of both CFRT and SBRT. The USC provides an empirically and a clinically well-justified rationale for SBRT while preserving the strengths of the LQ model for CFRT.

pubmed.ncbi.nlm.nih.gov

Second sentence of one of the reference abstracts: “Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery.”*

As far as I have seen, ALL of the data used to generate the model are obtained in vitro at doses WELL WITHIN those used in radiosurgery. (Look at any cell survival curve in Hall for starters.)

I don’t know how people can be taken seriously when they write fake news claims like this.

*by radiosurgery I would include SBRT, and by doses I would say 8-10Gy fractional dose size or larger

 

[communitydoc13]

(Look at any cell survival curve in Hall for starters.)

LQ model for clinical stuff is really based on clinical outcomes. You think an a/b for late myelopathy is roughly 3, it's based on clinical data (maybe animal data), not cell culture experiments.

Any cell culture stuff needs to be taken with a grain of salt. It describes a real phenomenon but the actual clinical endpoints are the result of so much more than cell survival in-vitro. There is plenty of cell culture work at high doses, this does not amount to the clinical endpoints that are used as the data set to generate an a/b.

Also, for any fit curve, one has to consider goodness of fit. How much variance is there? Is that variance increasing with increased dose? If it is, it means that you should be less confident in the fit to guide clinical decision making at those high doses.

 

[sirspamalot]

Error bars are like candy bars. Neither provides much nutrition once you start overlapping them over and over.

 

[TheWallnerus]

LQ model for clinical stuff is really based on clinical outcomes. You think an a/b for late myelopathy is roughly 3, it's based on clinical data (maybe animal data), not cell culture experiments.

Any cell culture stuff needs to be taken with a grain of salt. It describes a real phenomenon but the actual clinical endpoints are the result of so much more than cell survival in-vitro. There is plenty of cell culture work at high doses, this does not amount to the clinical endpoints that are used as the data set to generate an a/b.

Also, for any fit curve, one has to consider goodness of fit. How much variance is there? Is that variance increasing with increased dose? If it is, it means that you should be less confident in the fit to guide clinical decision making at those high doses.

Tell me where you have not seen an exponential increase in tumor kill or clinical side effects with linear increase in dose, varying fractional sensitivity depending on the tissue/tumor treated, etc. Leave the (voluminous, profound) in vitro studies out of mind. None of the things we see with our own eyeballs make sense without LQ. If something else makes better sense… what? If nothing else makes sense, let’s turn off the linacs because we are just experimenting on people.

 

[radiation]

Second sentence of one of the reference abstracts: “Much of the data used to generate the model are obtained in vitro at doses well below those used in radiosurgery.”*

As far as I have seen, ALL of the data used to generate the model are obtained in vitro at doses WELL WITHIN those used in radiosurgery. (Look at any cell survival curve in Hall for starters.)

I don’t know how people can be taken seriously when they write fake news claims like this.

*by radiosurgery I would include SBRT, and by doses I would say 8-10Gy fractional dose size or larger

just because its on the x axis, doesnt mean lots of data was actually collected for higher doses. dont be confused by fitted lines and extrapolated data points. Look at the actual graphs with experimental data. It is absolutely true the vast majority of collected experimental data is only for fraction sizes < 8 gy.

you probably have not had the pleasure of using an cell irradiator - the dose rate on those things are painfully slow. Part of the reason there are much fewer in vitro data for higher doses is because it was just a pain in the ass to deliver anything over 15 gy

 

[communitydoc13]

If something else makes better sense… what? If nothing else makes sense, let’s turn off the linacs because we are just experimenting on people

No reason to turn off the linacs, just reason not to come up with custom, single fraction, high dose SBRT prescriptions based on the LQ model. (again, not really even a model, more of a fit).

Please just do an EQD2 calc for an a/b 3 effect (call it late cord myelopathy) as you go from 15 Gy X1 to 16 Gy X1.

If you haven't done this, you will be shocked by the result.

If you have a lot of confidence in a fitted function with this type of change with change in domain (fraction size), I think you are not being appropriately cautious.

Now, play around with the same calculator using 3 fraction regimens in the domain of 7Gy to 10Gy per fraction. Wow, so much safer, so much gentler.

Even better so with 5 fractions.

Fractionation one of the best safety tools around.

 

[sirspamalot]

How's that song go again?

Fraction for me. Fraction for you. I love fractionssssssssssss... (but my sick elderly patients don't)

 

[communitydoc13]

How's that song go again?

Fraction for me. Fraction for you. I love fractionssssssssssss... (but my sick elderly patients don't)

Sick and elderly, 8Gy x 1, always safe. 3D plan.

For patients aiming for a year or more of life, looking at 30-50 onc visits during their remaining lifetime, going from 32 to 34 visits for meaningful safety is probably the right call.

 

[TheWallnerus]

No reason to turn off the linacs, just reason not to come up with custom, single fraction, high dose SBRT prescriptions based on the LQ model. (again, not really even a model, more of a fit).

Please just do an EQD2 calc for an a/b 3 effect (call it late cord myelopathy) as you go from 15 Gy X1 to 16 Gy X1.

If you haven't done this, you will be shocked by the result.

If you have a lot of confidence in a fitted function with this type of change with change in domain (fraction size), I think you are not being appropriately cautious.

Now, play around with the same calculator using 3 fraction regimens in the domain of 7Gy to 10Gy per fraction. Wow, so much safer, so much gentler.

Even better so with 5 fractions.

Fractionation one of the best safety tools around.

What’s weird is we are saying exact same thing, you’re using LQ to say it, and saying… don’t trust LQ. Heh.

 

[communitydoc13]

What’s weird is we are saying exact same thing, you’re using LQ to say it, and saying… don’t trust LQ. Heh.

Fair. I trust it within the 1.8-3 Gy per fraction range quite a bit. I trust it for large a/b effects (mostly linear) more than for small a/b effects (more quadratic). I use it all the time to find reasonable dose painting solutions or to moderately hypofractionate.

 

[TheWallnerus]

View attachment 363287


View attachment 363288


just because its on the x axis, doesnt mean lots of data was actually collected for higher doses. dont be confused by fitted lines and extrapolated data points. Look at the actual graphs with experimental data. It is absolutely true the vast majority of collected experimental data is only for fraction sizes < 8 gy.

you probably have not had the pleasure of using an cell irradiator - the dose rate on those things are painfully slow. Part of the reason there are much fewer in vitro data for higher doses is because it was just a pain in the ass to deliver anything over 15 gy

These graphs look great! Seem to support a linear-quadratic radiotherapy response. (Which becomes quadratic-linear when you graph on a log plot… see first graph… but I digress!)

Less than 8 Gy fraction doses are still definable as stereotactic. Wink. If the 8 Gy and higher fraction doses still fit with the lower dose data there was no need to run the pain in the ass irradiatiors at any more data-collecting frequency than at the lower fraction doses. Double wink.

 

[TheWallnerus]

Fair. I trust it within the 1.8-3 Gy per fraction range quite a bit. I trust it for large a/b effects (mostly linear) more than for small a/b effects (more quadratic). I use it all the time to find reasonable dose painting solutions or to moderately hypofractionate.

Let me make sure I still “got it.”

Large a/b effects (small cell eg) will vary *exponentially* with dose, which graphs linearly on a log plot. (Eg small cell has no shoulder on a log plot and small fraction sizes get as much “bang for buck” as large fraction sizes)

Small a/b effects (CNS eg) will vary linearly with dose and graphs exponentially on a log plot (at least at at smaller doses) and shows extreme fraction size sensitivity (which inversely correlates with the a/b)… but will ultimately vary exponentially with dose at much higher fraction sizes

 

[sirspamalot]