late GU toxicity

[winstonfoot5]

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Anyone have any good references showing that late GU toxicity may not be seen until 5-10 years of follow up? For example, those who are hesitant to employ hypofractionation always say we need longer follow up.

 

[Gfunk6]

In my view, the issue is not so much late GU toxicity as subacute financial toxicity from shifting from 44 fraction IMRT/protons to 28 (or less).




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[medgator]

In my view, the issue is not so much late GU toxicity as subacute financial toxicity from shifting from 44 fraction IMRT/protons to 28 (or less).



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Unlike breast hypoFx where the data would support that, prostate seems to have some real clinical risk. Are you going to call out people for financial motives when they choose not to hypofractionate/sbrt a guy with a 70cc prostate and AUA of 17?

http://ascopubs.org/doi/full/10.1200/jco.2016.67.0448

 

[Chartreuse Wombat]

Patient reported outcomes in 0415 referenced above were not different according to arm; CHHiP (n=3200) and PROFIT (n=1200) find no difference in physician reported or patient reported toxicity. The weight of the evidence supports no increased toxicity with moderate hypofractionation.

As usual GFunk is spot on

 

[Gfunk6]

These results were discussed at length by the authors during the ASTRO 2016 clinical trials session. There was a strong emphasis not to "over read" the results and that the delta between the two groups was so minuscule that it should be safely ignored in practice.

We are not talking about IMRT vs 3D. Is a theoretical 7% improvement in late Gr2 toxicity worth 3 weeks of someone's life and $20,000? Only in a system which rewards such behavior.

Not suggesting that we should robotically hypofrac/SBRT everyone but deviations should be the exception in my opinion.


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[medgator]

It looks great so far, don't get me wrong. But I'm still skeptical in baseline symptomatic patients.... would be nice if astro chooses to address this in their next "choosing wisely" campaign.


http://www.redjournal.org/article/S0360-3016(16)30349-2/abstract

I thought the zietman editorial on the issue was pretty good, especially the end, big fan of the last line lol:

http://ascopubs.org/doi/full/10.1200/jco.2016.67.3764

 

[Palex80]

We should await mature results. We only have 5 years of follow-up data. Many of us wanted towait out the 10 year aafety data on breast hypofractionation before switching. Why should it be different in prostate.

 

[seper]

treatment whose legacy may last a lifetime 🙂 well put

 

[Chartreuse Wombat]

We should await mature results. We only have 5 years of follow-up data. Many of us wanted towait out the 10 year aafety data on breast hypofractionation before switching. Why should it be different in prostate.

What is magic about 10 years? When there is 10 year data will you be asking for 15 year data?

Is there any reason to think that the toxicity curves will separate after 5 years? Yes, GU toxicity increases forever but what theory suggests that similarity at 5 years will be replaced by differences at 10 years.

Did you wait for 10 years of data to dose escalate? Dose escalation was adopted widely with clear evidence of a doubling of late toxicity with no survival benefit at all.

 

[RSAOaky]

Below is a link to the 0415 data.

http://ascopubs.org/doi/full/10.1200/jco.2016.67.0448

There was a statistically significant difference in Grade 2 GI and GU toxicity (11.4% vs. 18.3% for GI, p = 0.005; 20.5% vs. 26.2% for GU, p = 0.009). Grade 3 toxicity also appeared worse though there were few events and this was not SS. Toxicity was not an endpoint of this study. We sometimes minimize the impact of grade 2 toxicity on quality of life but some G2 toxicity is pretty awful.

As far as calling the toxicity difference "theoretical," this is a statistically significant difference and a pretty consistent one. Even in the QoL study there is a SS difference in bowel toxicity though "not clinically meaningful." We can spin the data any way we want based on our personal bias or incentives. As a large cooperative group perhaps the bias is to report data that is in line with their vision or that indicates that the trial was a success. As a private practice physician in a fee for service system, perhaps the incentive is to interpret this as a negative study with inferior toxicity outcomes. As a physician in a non fee for service model (i.e. Europe or academia) perhaps the bias is more in line with the RTOG. My take away from this is that it is by no means a slam dunk for hypofractionation though it may be a reasonable option in certain patients. Frankly, if I were a patient and you were to tell me that I'll have already met my deductible with the first 5 weeks of treatment and so for just 3 more weeks of my time there's a possibility that I'll have less toxicity I would go for the longer treatment in a heartbeat.

 

[medgator]

Did you wait for 10 years of data to dose escalate? Dose escalation was adopted widely with clear evidence of a doubling of late toxicity with no survival benefit at all.

To be fair, were those imrt/igrt studies with fiducials/cbct and 4-6 mm posterior margins?

 

[BobbyHeenan]

As I recall, the Pollock/Fox Chase trial also suggested patients with underlying AUA symptoms score > 12 showed worse GU toxicity profile. This was on post-hoc analysis though.

For me in my practice I have utilized 70 Gy in 28 fractions for probably the majority of patients over the past 18 months, but men with larger gland sizes (ie >60 cc) and especially those with IPSS > 12 I have used it more sparingly and tried to steer patients away if they have the ability to drive in for more fractions.

 

[radtothebone]

Personally, I think the RTOG study is the least useful to guide decision making. It was made up of primarily low risk patients (whom are rarely treated today) and had a standard dose (73.8 Gy) that I doubt any of us use frequently. CHHiP and PROFIT are much more akin to modern radiation therapy (one with ADT, one mostly without). Neither of those studies showed a hint of difference in late toxicity rates, except in PROFIT where Hypofrac appears favorable over standard frac.

I think the concerns about those with higher IPSS scores are reasonable and I have heard that subset analysis on these patients is coming from CHHiP. I have been offering hypofractionation to all my patients and just council those with IPSS >15-20 that they may have more long-term side effects compared to standard fractionation. My very unscientific observation has been there is no obvious toxicity difference compared to 8-9 weeks of treatment.

Like GFUNK says, bundled payments may force the hands of some. Also, I believe we will have a similar conversation in 5-7 years about SBRT and it's replacement of Hypofrac. Of course, bundled payments may also bring about a resurgence for brachytherapy, which I fear remains underappreciated

 

[RSAOaky]

Take it with a grain of salt but, per the discussion section regarding the dose, "this dose was specified such that > 98% of the prostate received ≥ 73.8 Gy. Because the protocol allowed ≤ 7% inhomogeneity, portions of the prostate received doses > 76 Gy."

It's interesting how much lower the overall toxicity rate is in the CHHiP study: "The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively."

 

[Palex80]

What is magic about 10 years? When there is 10 year data will you be asking for 15 year data?

Is there any reason to think that the toxicity curves will separate after 5 years? Yes, GU toxicity increases forever but what theory suggests that similarity at 5 years will be replaced by differences at 10 years.

Did you wait for 10 years of data to dose escalate? Dose escalation was adopted widely with clear evidence of a doubling of late toxicity with no survival benefit at all.

Nothing is "magical" about 10 years.
The chance that a difference will be observed at 15 years is low, if there's no difference at 10 years.

Dose escalation did result in better PFS, that's why we adopted it. Hypofractionation in PCA has so far resulted only in less appointments and costs fot the patients. No clinical benefit so far.

 

[Haybrant]

i think there should be some concern about SBRT w regards to dose per fraction to the trigone. But agree w Ggunk if we were in a single payer system this would be adopted quite fast and applauded. When will we go to single payer? We're crazy not to support this. At this point you have to question 100% of what the older generation of physicians have taught you with regard to all treatments you administer.

 

[medgator]

. When will we go to single payer? We're crazy not to support this. At this point you have to question 100% of what the older generation of physicians have taught you with regard to all treatments you administer.

Reference what RSAoaky said above. He nailed it perfectly in describing the issue in a pp environment, and no it's not just about $$$$

This isn't breast cancer where the data has much longer follow-up and the hypofx data actually looks better than standard.

The data isn't as mature and there are concerns regarding toxicity esp in patients with larger glands and/or higher baseline aua scores.

In a competitive pp environment, the only reason to jump into this is if the payors are pushing you into it, otherwise, why take the risk of being more toxic than the other guy in town?

 

[Haybrant]

Reference what RSAoaky said above. He nailed it perfectly in describing the issue in a pp environment, and no it's not just about $$$$

This isn't breast cancer where the data has much longer follow-up and the hypofx data actually looks better than standard.

The data isn't as mature and there are concerns regarding toxicity esp in patients with larger glands and/or higher baseline aua scores.

In a competitive pp environment, the only reason to jump into this is if the payors are pushing you into it, otherwise, why take the risk of being more toxic than the other guy in town?

Ok I actually do agree with this. But in single payer you can do as you will - nobody will be over your head trying to get you to reduce # of treatments either (ie bundle care). The time for single payer is now. Either obamacare (which is a total sham to get hard working middle class to pay into insurance overtreatment and using avastin for BS) or trumpcare will blow up and single payer will emerge as the only option.

 

[medgator]

. Either obamacare (which is a total sham to get hard working middle class to pay into insurance overtreatment and using avastin for BS) or trumpcare will blow up and single payer will emerge as the only option.

Completely agree. Even insurance company CEOs know this.

Until then, I don't see the data to be as compelling as it is in breast. Again, this is market dependent. There are some PPs I know of that are offering prostate sbrt off protocol to compete with other groups and/or urorads in their geographic area

 

[MegaVoltagePhoton]

What's the longest published series for late GU toxicity after dose-escalated IMRT (hint: it's probably not as long as you think)? How much followup is there, and how much would you want to see before the bogeyman could be put to rest?

People are talking as if we have this well known gold standard figure for what SBRT's late toxicity should be, when we don't even have great data for >10 year IMRT toxicities. Also, the series that have had bad toxicity with SBRT were generally ones where there was some kind of technical issue or the dose was too high.

I mean, use the lack of followup as a defense if you want, but realize the same issue exists with things you probably do anyway.

 

[radiaterMike]

Perhaps the difference is that there are longterm data with conventional fractionation. IMRT is a means to deliver radiation (in any fractionation scheme).


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[MegaVoltagePhoton]

Perhaps the difference is that there are longterm data with conventional fractionation. IMRT is a means to deliver radiation (in any fractionation scheme).


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You're right, my post was vague. I meant, of course, dose-escalated IMRT and not just IMRT. The followup of the MDACC trial (which has a true "PTV" dose of closer to 75.6 Gy) is not super long. Zelefsky's 81 Gy (let along 86.4 Gy) data doesn't have >10 year true followup, either. We accept it anyway.

 

[medgator]

Hot off the presses....

http://ascopubs.org/doi/abs/10.1200/JCO.2016.71.7397

"Most late events with moderate hypofractionation occurred within the first 48 months. Occasionally, very late bladder events occurred with hypofractionated doses higher than those used in the Prostate Fractionated Irradiation Trial (PROFIT). However, patients in the current trial should be followed for at least 10 years."

http://ascopubs.org/doi/full/10.1200/JCO.2017.72.7016

"How is moderate hypofractionation likely to be adopted in the United States? From our experience with breast cancer, hypofractionation likely will not accelerate until longer-term data are reported. After the 10-year follow-up of the Canadian breast fractionation data11 and long-term outcomes of the UK Standardisation of Breast Radiotherapy (START-A) and START-B trials was when national guidelines began to encourage routine and widespread use.12Even then, adoption was variable.13 Nonetheless, if the current data hold with longer follow-up, the drumbeat of adoption likely will become impossible to ignore."

"For some, the weight of evidence now favors moderate hypofractionation as a safe, equivalently effective, and more convenient option to conventional fractionation. For others, only time will tell."