RTOG prostate hypofrac toxicity

[Krukenberg]

I’m considering switching to 60/20 from 70/28 due to the higher late toxicity in 0415. The ASTRO guideline suggests that the higher toxicity might have been due to the extremely lax OAR goals on the trial.

Is anyone aware of data published from 0415 showing that actual treatment plans on the trial were coming close to the OAR goals? Our plans blow those goals out of the water, but if patients treated in the trial were also blowing the goals out of the water, I’ll feel more compelled to switch to 60/20.

@Chartreuse Wombat
@ramsesthenice

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[BobbyHeenan]

I’m considering switching to 60/20 from 70/28 due to the higher late toxicity in 0415. The ASTRO guideline suggests that the higher toxicity might have been due to the extremely lax OAR goals on the trial.

Is anyone aware of data published from 0415 showing that actual treatment plans on the trial were coming close to the OAR goals? Our plans blow those goals out of the water, but if patients treated in the trial were also blowing the goals out of the water, I’ll feel more compelled to switch to 60/20.

@Chartreuse Wombat
@ramsesthenice

This doesn't answer your question, but...

Off the top of my head, I think in line with what you're saying, there's a Kupelian paper (around 2005) that suggested the best predictor for late rectal toxicity with 70/28 was the volume of rectum getting 70 Gy. They suggested definitely needed V70 < 10 cc. We stressed this in my training. 0415 as I recall did not have this as a strict dose constraint.

I try to get V70 Gy < 5 cc, and I can usually get it around 2-4 cc with 100% of Rx covering 95% of PTV. Sometimes < 1 cc if spaceOAR. I don't mandate spaceOAR.

Very anecdotal: I've been doing more 60/20 and anecdotally haven't seen much diffference overall in toxicity between it and 70/28. One exception I have seen is that the acute GU toxicity as expected kind of ramps up quicker and peaks after radiation is over in the 60/20. A few guys told me was pretty rough week 1 after xrt over and hit them pretty hard/quick in the last week of radiation . Usually 70/28 seems to come on a bit slower (but not as slow as 2 gy/fraction).

 

[Krukenberg]

This doesn't answer your question, but...

Off the top of my head, I think in line with what you're saying, there's a Kupelian paper (around 2005) that suggested the best predictor for late rectal toxicity with 70/28 was the volume of rectum getting 70 Gy. They suggested definitely needed V70 < 10 cc. We stressed this in my training. 0415 as I recall did not have this as a strict dose constraint.

I try to get V70 Gy < 5 cc, and I can usually get it around 2-4 cc with 100% of Rx covering 95% of PTV. Sometimes < 1 cc if spaceOAR. I don't mandate spaceOAR.

Very anecdotal: I've been doing more 60/20 and anecdotally haven't seen much diffference overall in toxicity between it and 70/28. One exception I have seen is that the acute GU toxicity as expected kind of ramps up quicker and peaks after radiation is over in the 60/20. A few guys told me was pretty rough week 1 after xrt over and hit them pretty hard/quick in the last week of radiation . Usually 70/28 seems to come on a bit slower (but not as slow as 2 gy/fraction).

Yea RTOG 70/28 rectum goal was V69Gy<25% and V74Gy<15%.

Page 10 https://www.ncbi.nlm.nih.gov/pmc/ar...upp_JCO.2016.67.0448_Protocol_2016.670448.pdf

 

[seper]

Yes, when you do 70/28fx, you can and should push constraints harder than on protocols.
Also, use nodal irradiation judiciously

 

[BobbyHeenan]

Yes, when you do 70/28fx, you can and should push constraints harder than on protocols.
Also, use nodal irradiation judiciously

Yes. I 100% see wwaayy more gi toxicity in my high risk patients I do 70/28 with 50.4 to nodes.

 

[Krukenberg]

Yes, when you do 70/28fx, you can and should push constraints harder than on protocols.
Also, use nodal irradiation judiciously

Absolutely. My question is did clinicians push constraints harder on trial as well. If so, that suggests to me that 70/28 probably is more toxic than 60/20. If clinicians were super lax because the constraints were lax, then I’d feel more confident that 70/28 is most likely equivalent to 60/20 if you push constraints.

 

[OTN]

Yes. I 100% see wwaayy more gi toxicity in my high risk patients I do 70/28 with 50.4 to nodes.

So why do it?

 

[BobbyHeenan]

So why do it?

I struggle with that too. Inertia from training and Pop_RT trial I guess...

 

[communitydoc13]

Yes. I 100% see wwaayy more gi toxicity in my high risk patients I do 70/28 with 50.4 to nodes.

Just do a CD when you feel prophy nodal tx necessary (which some people never do). 62.5/45 and 3 fraction CD to prostate/SV. I agree that in a site where prophy nodal treatment questionable, escalating prophylactic nodal dose makes little sense.

 

[BobbyHeenan]

Just do a CD when you feel prophy nodal tx necessary (which some people never do). 62.5/45 and 3 fraction CD to prostate/SV. I agree that in a site where prophy nodal treatment questionable, escalating prophylactic nodal dose makes little sense.

Ill have to look into that. That's a good thought.

In general, I am really lax on nodal coverage though to spare bowel.

 

[TheWallnerus]

Yea RTOG 70/28 rectum goal was V69Gy<25% and V74Gy<15%.

Page 10 https://www.ncbi.nlm.nih.gov/pmc/ar...upp_JCO.2016.67.0448_Protocol_2016.670448.pdf

FWIW I would hard reject rectal V69<25% (ie V69 20%? No way) as acceptable even when I’m going to 80+ Gy.

 

[Ray D. Ayshun]

V65<10% for me with <10cc getting prescription dose. Usually don't come close to violating those, and don't have much rectal toxicity.

 

[medgator]

So why do it?

Gets back what has been true all along...

Hypofx isn't a better treatment for prostate cancer, just quicker and cheaper, unlike what we've seen in N0 breast cancer

 

[Chartreuse Wombat]

I’m considering switching to 60/20 from 70/28 due to the higher late toxicity in 0415. The ASTRO guideline suggests that the higher toxicity might have been due to the extremely lax OAR goals on the trial.

Is anyone aware of data published from 0415 showing that actual treatment plans on the trial were coming close to the OAR goals? Our plans blow those goals out of the water, but if patients treated in the trial were also blowing the goals out of the water, I’ll feel more compelled to switch to 60/20.

@Chartreuse Wombat
@ramsesthenice

I know of no data in this regard. Remember that 0415 was designed very early in the IMRT era and the constraints were extremely liberal compared with what are recommended more recently (see link below)

Six Questions to Ask Before We Shorten Radiation Treatments for Intact Prostate Cancer - PubMed

Six Questions to Ask Before We Shorten Radiation Treatments for Intact Prostate Cancer

pubmed.ncbi.nlm.nih.gov

The other thing to keep in mind is that the comparator arm of 0415 (73.8/41) was lower than the comparator in CHHiP (74/37) and much lower than the comparator in PROFIT (78/39).

RTOG 0126 compared 70.2 to 79.2 in 1.8 Gy fractions and one expects that the toxicity of 73.8 lies somewhere between 70 and 79.2. So if you are using 79.2 Gy then one would expect greater toxicity than 73.8 Gy which could rebut the argument that there is more toxicity with moderate hypofractionation.

 

[Wildcat321]

I know of no data in this regard. Remember that 0415 was designed very early in the IMRT era and the constraints were extremely liberal compared with what are recommended more recently (see link below)

Six Questions to Ask Before We Shorten Radiation Treatments for Intact Prostate Cancer - PubMed

Six Questions to Ask Before We Shorten Radiation Treatments for Intact Prostate Cancer

pubmed.ncbi.nlm.nih.gov

The other thing to keep in mind is that the comparator arm of 0415 (73.8/41) was lower than the comparator in CHHiP (74/37) and much lower than the comparator in PROFIT (78/39).

RTOG 0126 compared 70.2 to 79.2 in 1.8 Gy fractions and one expects that the toxicity of 73.8 lies somewhere between 70 and 79.2. So if you are using 79.2 Gy then one would expect greater toxicity than 73.8 Gy which could rebut the argument that there is more toxicity with moderate hypofractionation.

This is the best I could find:

Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of …

www.sciencedirect.com

 

[Chartreuse Wombat]

This is the best I could find:
View attachment 350091

Tolerance doses for late adverse events after hypofractionated radiotherapy for prostate cancer on trial NRG Oncology/RTOG 0415

Hypofractionated radiotherapy (HRT) regimens for prostate cancer are emerging, but tolerance doses for late adverse events are scarce. The purpose of …

www.sciencedirect.com

"Late GI toxicity, following moderate HRT for low-risk prostate cancer, increases with higher doses to small rectal volumes."

As with conventional fractionation it is the high dose that is associated with toxicity; moderate doses seem to matter less.

?Proton people what say you?

 

[deleted1111261]

Is there institutional data with tighter constraints used ?

 

[RickyScott]

All the constraints are based on a completely empty rectum, otherwise they are worthless? In the real world, pts not always simmed with an empty rectum which is why I prefer looking at rate of falloff.

 

[OTN]

You could also make another change to improve rectal toxicity

 

[Ray D. Ayshun]

Saw this on themednet:

theMednet

Thoughts?

 

[communitydoc13]

You could also make another change to improve rectal toxicity

Yep, well known that acute toxicity reflects dose per fraction and duration of treatment course. Of course when you are using palliative dosing, this doesn't hold, but for definitive treatment of carcinomas, clear as day.

This context, where we are collectively encouraged (it has become more than encouraged) to treat as short a course as reasonable and accept an increase in acute toxicity, contributes to skepticism regarding expensive interventions like MRI guided tx or SPACEOAR.

At what point do you lose the value based argument or QOL argument with this approach?

 

[medgator]

Yep, well known that acute toxicity reflects dose per fraction and duration of treatment course. ....

At what point do you lose the value based argument or QOL argument with this approach?

That didn't hold true for breast HF vs CF.

Acute and Short-term Toxic Effects of Fractionated Breast Irradiation

In this randomized clinical trial, hypofractionated whole-breast irradiation (WBI) appeared to yield lower rates of acute toxic effects than conventionally fractionated WBI as well as less fatigue and less trouble meeting family needs 6 months after radiation therapy.

jamanetwork.com

I continue to have 0 guilt in offering CF prostate IMRT as an option with HF. None. There's a reason why the Astro guidelines for prostate hf aren't a full throated endorsement like they are for breast

 

[communitydoc13]

That didn't hold true for breast HF vs CF.

Adjuvant dosing not definitive dosing. If we were dumping 75 Gy vs 40 Gy in 5 fractions the difference would be clear. (Hell, even the data used to justify ultra hypo whole breast shows a (peculiar threshold phenomenon....I'm calling BS) with 26 vs 27 Gy.

 

[RickyScott]

That didn't hold true for breast HF vs CF.

Acute and Short-term Toxic Effects of Fractionated Breast Irradiation

In this randomized clinical trial, hypofractionated whole-breast irradiation (WBI) appeared to yield lower rates of acute toxic effects than conventionally fractionated WBI as well as less fatigue and less trouble meeting family needs 6 months after radiation therapy.

jamanetwork.com

I continue to have 0 guilt in offering CF prostate IMRT. None. There's a reason why the Astro guidelines for prostate hf aren't a full throated endorsement like they are for breast

Over the past year, I have had 2 men who required catheters because I was overzealous w/hypofract. Never happened before. Most of my pts live nearby and choose cf.

 

[medgator]

Adjuvant dosing not definitive dosing. If we were dumping 75 Gy vs 40 Gy in 5 fractions the difference would be clear. (Hell, even the data used to justify ultra hypo whole breast shows a (peculiar threshold phenomenon....I'm calling BS) with 26 vs 27 Gy.

Dose is dose, regardless of the indication. The breast is far more forgiving than a walnut sized organ sandwiched between two very important body outlets

 

[medgator]

Over the past year, I have had 2 men who required catheters because I was overzealous w/hypofract. Never happened before. Most of my pts live nearby and choose cf.

Have not seen the GU tox as bad as the GI toxicity (which is what is seen in multiple trials). Had one pt recently with pretty bad diarrhea that needed a week break towards the end, was never an issue with CF. I still offer HF but counsel regarding the tradeoffs and risks as mentioned in the ASTRO statement

 

[communitydoc13]

Dose is dose, regardless of the indication

I disagree, when you are down around an EQD2 of 40-55 the impact of fractionation change on toxicity may be much different than when your EQD2 is 70-80. Just different dose regimes where acute toxicity and likely consequential late effects are going to respond differently to dose schedule modification IMO.

Time factor itself is probably most important. Time independent EQD2 calcs for the prostate regimens (and breast) show lower equivalent dose for high a/b in most hypofractionated regimens.

 

[deleted1111261]

On a re - reading of the literature, I think I’m backing off in saying that moderate should be The Standard. I generally don’t do CF or even talk about it, but I get it if you do.

 

[TheWallnerus]

Over the past year, I have had 2 men who required catheters because I was overzealous w/hypofract.

I got 99 problems but that ain't one

 

[RickyScott]

I got 99 problems but that ain't one

Cath taken out after a few days, but both guys retired and lived nearby so what is accomplished by hypofract?

 

[TheWallnerus]

Cath taken out after a few days, but both guys retired and lived nearby so what is accomplished by hypofract?

PROBLEMS!

 

[evilbooyaa]

On a re - reading of the literature, I think I’m backing off in saying that moderate should be The Standard. I generally don’t do CF or even talk about it, but I get it if you do.

So you don't counsel patients that there is a treatment that offers them lower risk of acute GI toxicity (reminder that that's what MIRAGE showed), and otherwise equivalent outcomes (oncologic and toxicity), but it just means making more trips for radiation? I think all prostate patients should be OFFERED CF, even if 80% will take the tradeoff and do something else due to convenience sake.

Saw this on themednet:

theMednet

Thoughts?

Dr. Anscher is old school and thus prefers conventional in nearly every scenario. So, this response is inline with his thinking. Most of his MedNet answers talk about the (mostly unproven, IMO) dangers of hypofractionation.

 

[Mandelin Rain]

I've definitively seen more acute obstructive symptoms with 60/20 regimen than ever before. Luckily never lead to a cath, but Flomax is flowing and ibuprofen TID had become a thing. I've since backed off to 70/28 for guys with anything more than mild baseline symptoms. No evidence for it. Just felt like I had to do something.

 

[Mandelin Rain]

So you don't counsel patients that there is a treatment that offers them lower risk of acute GI toxicity (reminder that that's what MIRAGE showed), and otherwise equivalent outcomes (oncologic and toxicity), but it just means making more trips for radiation? I think all prostate patients should be OFFERED CF, even if 80% will take the tradeoff and do something else due to convenience sake.



Dr. Anscher is old school and thus prefers conventional in nearly every scenario. So, this response is inline with his thinking. Most of his MedNet answers talk about the (mostly unproven, IMO) dangers of hypofractionation.

The issue is, how many things can you "offer" a guy for prostate cancer? It's dizzying. Like a typical low intermediate risk guy...... Are you really discussing pro- and cons- of active surveillance, surgery (robotic vs open), brachy (LDR vs HDR), beam (SBRT vs moderate hypo vs conventional), short course ADT (+ vs -), SpaceOAR vs Enema vs Balloon vs whatever, Fiducials vs CBCT alone? Say nothing of the nonstandard treatment they have have read about.

It's like a 3 hour event if you do that, and the patient tabs you as an indecisive waffler and sees someone else. I think at some point it's reasonable to pick what your standard is and offer that.

 

[deleted1111261]

So you don't counsel patients that there is a treatment that offers them lower risk of acute GI toxicity (reminder that that's what MIRAGE showed), and otherwise equivalent outcomes (oncologic and toxicity), but it just means making more trips for radiation? I think all prostate patients should be OFFERED CF, even if 80% will take the tradeoff and do something else due to convenience sake.



Dr. Anscher is old school and thus prefers conventional in nearly every scenario. So, this response is inline with his thinking. Most of his MedNet answers talk about the (mostly unproven, IMO) dangers of hypofractionation.

Yes, exactly. It is a standard and it is my standard. That is okay for me to have a standard, too, right? Just like the 98% + radoncs that breeze by 8 Gy in 1 as an option (including the fact that 80-90% of them won't have to get re-treated)? Just like the 98% of doctors that aren't offering 5fx VMAT PBI, even though it's probably less toxic?

Like I said, in this case, it is reasonable to use 1.8 Gy. I get that. It's not what I think is best and though the data shows that increased toxicity, with image guidance, tight margins, and tighter constraints, I don't see the issues that you all are talking about. I did have a bit more urinary symptoms with 60/20, so not doing that very much any more.

The other part is - I don't buy that the majority of doctors that "offer" both are doing a fair job. I asked a few what they tell them, whether they tell them what the additional toxicity is, how many more patients get that toxicity and they were unable to quantify this. So, just saying one has "more" toxicity and the other has less treatments is not a discussion. So, yeah, in conclusion, I don't think most people are truly discussing both. They know what they want to give and give that.

 

[deleted1111261]

I've definitively seen more acute obstructive symptoms with 60/20 regimen than ever before. Luckily never lead to a cath, but Flomax is flowing and ibuprofen TID had become a thing. I've since backed off to 70/28 for guys with anything more than mild baseline symptoms. No evidence for it. Just felt like I had to do something.

Yes! 60/20 - I see the urinary symptoms that you are describing.

 

[metallica81788]

When I first arrived at my job, I was offering 70/28 or 60/20 to everyone but high risk where I did standard fractionation (that's how I trained).
I was even fraction-shamed a few time at chart rounds early on by not 70/28ing everyone so I converted essentially out of peer pressure.

However, now I'm seeing more acute GU obstructive type symptoms than I would have expected with my hypofrac crowd compared to conventional. 70/28 is still my "standard" but I give everyone AUA scores at consult and will not hesitate to tell them if I think they should get conventional for various reasons. A lot of people still choose the convenience of less treatments.

Most of my prostate consults take the full hour unless they already know they don't want surgery or are non-operative candidates.

 

[salubalu]

I do SBRT for almost all my prostates for the last three years and I’ve been happy with my outcomes and toxicity profile.

 

[TheWallnerus]

Dr. Anscher is old school and thus prefers conventional in nearly every scenario. So, this response is inline with his thinking.

I've definitively seen more acute obstructive symptoms with 60/20 regimen than ever before. Luckily never lead to a cath, but Flomax is flowing and ibuprofen TID had become a thing. I've since backed off to 70/28 for guys with anything more than mild baseline symptoms.

Like I said, in this case, it is reasonable to use 1.8 Gy.

Some people have shown that conventional fractionation (ie 81/45) helps prostate patients with bad urinary symptoms.

 

[CodeRedDew]

I do SBRT for almost all my prostates for the last three years and I’ve been happy with my outcomes and toxicity profile.

SpaceOAR? What image guidance are you using?

 

[salubalu]

SpaceOAR? What image guidance are you using?

I offer space oar to all insurance permitting. Cyberknife with fiducials. In residency we really only did conventional or conventional with brachy boost but after graduating I joined a group that was doing SBRT for about 10 years. I’ve been happy with it in regards to toxicity and outcomes.

 

[thesauce]

The issue is, how many things can you "offer" a guy for prostate cancer? It's dizzying. Like a typical low intermediate risk guy...... Are you really discussing pro- and cons- of active surveillance, surgery (robotic vs open), brachy (LDR vs HDR), beam (SBRT vs moderate hypo vs conventional), short course ADT (+ vs -), SpaceOAR vs Enema vs Balloon vs whatever, Fiducials vs CBCT alone? Say nothing of the nonstandard treatment they have have read about.

It's like a 3 hour event if you do that, and the patient tabs you as an indecisive waffler and sees someone else. I think at some point it's reasonable to pick what your standard is and offer that.

It takes me about 1.5 hours now that I’ve got the spiel down, but yes I do - every single time

 

[Ray D. Ayshun]

The issue is, how many things can you "offer" a guy for prostate cancer? It's dizzying. Like a typical low intermediate risk guy...... Are you really discussing pro- and cons- of active surveillance, surgery (robotic vs open), brachy (LDR vs HDR), beam (SBRT vs moderate hypo vs conventional), short course ADT (+ vs -), SpaceOAR vs Enema vs Balloon vs whatever, Fiducials vs CBCT alone? Say nothing of the nonstandard treatment they have have read about.

It's like a 3 hour event if you do that, and the patient tabs you as an indecisive waffler and sees someone else. I think at some point it's reasonable to pick what your standard is and offer that.

Agreed. Wish we could ban the word "offer" from our lexicon. Makes me sound like a GM and not a coach.

 

[metallica81788]

Agreed. Wish we could ban the word "offer" from our lexicon. Makes me sound like a GM and not a coach.

This is another unspoken advantage our predecessors had over us - less options. Patient was a passenger in the vessel; the doctor told them treatment they were getting. No choices really, once they (maybe) made it past surgery vs radiation. And they were grateful.

Now we have endless options for radiation. It would be so much easier if they walked in and we told them "this is how it is" - I guess some still do.

I'm aware people are still around that do this and probably have faster clinic/consult throughput on the potentially time-sucking issues like prostate but I guess I'm not there yet. Some days I'd like to be there, some days glad I'm not.

 

[jondunn]

we told them "this is how it is" - I guess some still do.

many many many do

 

[Ray D. Ayshun]

This is another unspoken advantage our predecessors had over us - less options. Patient was a passenger in the vessel; the doctor told them treatment they were getting. No choices really, once they (maybe) made it past surgery vs radiation. And they were grateful.

Now we have endless options for radiation. It would be so much easier if they walked in and we told them "this is how it is" - I guess some still do.

I'm aware people are still around that do this and probably have faster clinic/consult throughput on the potentially time-sucking issues like prostate but I guess I'm not there yet. Some days I'd like to be there, some days glad I'm not.

Of course. Most have already had a long discussion. All have already seen urology, and heard about surgery, so I don't rehash in great detail. But "offer?"

 

[deleted1111261]

This is another unspoken advantage our predecessors had over us - less options. Patient was a passenger in the vessel; the doctor told them treatment they were getting. No choices really, once they (maybe) made it past surgery vs radiation. And they were grateful.

Now we have endless options for radiation. It would be so much easier if they walked in and we told them "this is how it is" - I guess some still do.

I'm aware people are still around that do this and probably have faster clinic/consult throughput on the potentially time-sucking issues like prostate but I guess I'm not there yet. Some days I'd like to be there, some days glad I'm not.

I am curious how the change to "patient centered decision making" has benefited / harmed patient.

A healthy bit of paternalism is not a bad thing. Or, should we say maternalism? But, yeah, giving your opinion is not a bad thing.

 

[Mandelin Rain]

Of the two people in the room, you’re ether one with 9 years of medical training including 4 years of radiation oncology specific training. You’re the one being paid for this expertise.

To layout 15 “options” and let the patient order from your menu doesn’t make you a good, caring, enlightened doctor. It makes you a detached participant. Like a bad waiter.

 

[deleted1111261]

Of the two people in the room, you’re ether one with 9 years of medical training including 4 years of radiation oncology specific training. You’re the one being paid for this expertise.

To layout 15 “options” and let the patient order from your menu doesn’t make you a good, caring, enlightened doctor. It makes you a detached participant. Like a bad waiter.

Perfect analogy.

"What's good here?"

"Oh - everything is just delicious! What do you like?"

Gimme a freakin' recommendation. I know there are like 10 things on this menu you wouldn't feed to your enemy.

 

[metallica81788]

Giving your recommendation is important - it's not 100% "you choose" and there has been devaluation of our expertise as a field and as doctors in general which is very frustrating.

The variable is how you get there. Do you just come in guns blazing "here's what we're doing" or do you lay out things and have reasonable pathway to decision. Some patients need the "here's what is happening" talk and others are capable of choosing.

From a financial standpoint, I could certainly get paid more if I told all prostates conventional fractionation and offered no hypofrac - they'd get cured just the same but it would be a change from what I normally do. It would be like the waiter only recommending the huge prime rib for their tip even though it still may be the best thing on the menu - both things can co-exist.