Adjuvant vs Salvage RT in Prostate cancer.... again

[Palex80]

https://x.com/5_utr/status/1715530916397752622

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[drowsy12]

Guy is unhinged.

 

[evilbooyaa]

He's passionate but seemingly aggressive. Pretty classy response from Chris Parker.

 

[thecarbonionangle]

https://x.com/5_utr/status/1715530916397752622

View attachment 378059

Whoever this person is, im not a fan of their posts. They seem pompous and rude. I saw him come after CS once on APBI. Not a good look for our field. They used to go by “5-UTR” as their name

 

[drowsy12]

Whoever this person is, im not a fan of their posts. They seem pompous and rude. I saw him come after CS once on APBI. Not a good look for our field. They used to go by “5-UTR” as their name

That’s still the name of his account

 

[elementaryschooleconomics]

He's passionate but seemingly aggressive. Pretty classy response from Chris Parker.

Just totally randomly, and this is unfortunately calling myself out for how much I pay attention to SDN and for how long, but:

Radiation Oncology must truly be on the ropes if @evilbooyaa is posting on the weekend.

 

[sirspamalot]

This needs to play at next ASTRO meeting every time someone does something stupid.

 

[TheWallnerus]

Whoever this person is, im not a fan of their posts. They seem pompous and rude.

Prob a Zapf Dingbats in the tweets and a Times New Roman in the streets. Imagine running an international phase III trial set to define practice and having some anonymous yayhoo roll up on twitter saying you feloniously misinterpreted your results.

 

[elementaryschooleconomics]

Prob a Zapf Dingbats in the tweets and a Times New Roman in the streets. Imagine running an international phase III trial set to define practice and having some anonymous yayhoo roll up on twitter saying you feloniously misinterpreted your results.

The internet: an existential threat to the human race.

Instant communication to anyone, anywhere, 24/7.

The "pro" is the exact same as the "con".

Will we survive?

Let's do a Twitter poll.

 

[pikachu]

Whoever this person is, im not a fan of their posts. They seem pompous and rude. I saw him come after CS once on APBI. Not a good look for our field. They used to go by “5-UTR” as their name

“their”…”they”… “oh who am i kidding it’s a dude”

 

[thecarbonionangle]

“their”…”they”… “oh who am i kidding it’s a dude”

 

[evilbooyaa]

Just totally randomly, and this is unfortunately calling myself out for how much I pay attention to SDN and for how long, but:

Radiation Oncology must truly be on the ropes if @evilbooyaa is posting on the weekend.

Man... getting called out!

 

[DoctwoB]

https://x.com/5_utr/status/1715530916397752622

View attachment 378059

This trial poses an interesting statistical and ethical question in my view.

Say we were to accept these results as true, that adjuvant had an improvement in MFS over salvage in ITT analysis. This is a circumstance where the per-protocol analysis would be equally if not more important to me, because I find that with such a small different it is highly likely that any difference between the two curves is related to the 58 out of 286 patients with PSA progression in the salvage arm who didn't receive salvage XRT. The counter to this, is that we know in the real world patients often don't receive optimal salvage xrt, and almost certainly do so at a lower rate then they did in the trial.

However, If salvage xrt performed according to protocol is equally effective as adjuvant xrt, is it ethical to "overtreat" 60% of your patients (the percentage that had no psa progression, will vary based on population) to optimally treat those who would not otherwise receive adequate salvage due to patient or physician factors? If we try to select patients for adjuvant radiotherapy based on your assessment of their likelihood to receive optimal salvage, that introduces the potential for all sorts of cognitive biases.

Personally my view is that I discuss (and document) the discussion and let the patient select, of which almost all will select salvage, of which some will get suboptimal care due to their own lack of follow up. Actions have consequences, and I'm not willing to recommend overtreatment of many to prevent self-inflicted harm to the few.

 

[evilbooyaa]

If there is actually a MFS benefit of adjuvant RT compared to not adjuvant (forget whether it's salvage vs not receiving RT at all), then yes, adjuvant therapy is warranted in anyone who is at signficant risk of being lost to follow-up.

This is why we still recommend adjuvant RT or chemo for stage I seminoma who is not going to do surveillance properly.

We 'over-treat' the vast majority of patients who get adjuvant therapy to improve local recurrence, QOL, all sorts of endpoints that aren't overall survival in lots of clinical scenarios outside of prostate cancer. Metastasis-free survival in prostate cancer is a predictor of overall survival.

Combine this with the fact that people are extrapolating RADICALS/RAVES to Gleason 9+ disease patients (when most of these patients were Gleason 7) and I think there needs to be some serious questions about adjuvant RT.

You are looking at prostate cancer in a vaccuum, not realizing (through no fault of your own) that adjuvant therapy with radiation (across all cancers) has pretty much always worked exactly the way you are describing (and feeling discomfort with).

The unique issue with prostate cancer is that there is a toxicity of surgery (urinary incontinence) can persist for upwards of 3-6 months until peak recovery, which is such an extreme outlier compared to other post-surgical situations where we are routinely delivering radiation therapy. And then there's a concern that delivering radiation will 'stop' recovery of that toxicity.

 

[Chartreuse Wombat]

If there is actually a MFS benefit of adjuvant RT compared to not adjuvant (forget whether it's salvage vs not receiving RT at all), then yes, adjuvant therapy is warranted in anyone who is at signficant risk of being lost to follow-up.

This is why we still recommend adjuvant RT or chemo for stage I seminoma who is not going to do surveillance properly.

We 'over-treat' the vast majority of patients who get adjuvant therapy to improve local recurrence, QOL, all sorts of endpoints that aren't overall survival in lots of clinical scenarios outside of prostate cancer. Metastasis-free survival in prostate cancer is a predictor of overall survival.

Combine this with the fact that people are extrapolating RADICALS/RAVES to Gleason 9+ disease patients (when most of these patients were Gleason 7) and I think there needs to be some serious questions about adjuvant RT.

You are looking at prostate cancer in a vaccuum, not realizing (through no fault of your own) that adjuvant therapy with radiation (across all cancers) has pretty much always worked exactly the way you are describing (and feeling discomfort with).

The unique issue with prostate cancer is that there is a toxicity of surgery (urinary incontinence) can persist for upwards of 3-6 months until peak recovery, which is such an extreme outlier compared to other post-surgical situations where we are routinely delivering radiation therapy. And then there's a concern that delivering radiation will 'stop' recovery of that toxicity.

I disagree that MFS predicts survival in the postoperative setting. Happy to be corrected but my understanding is that none of the trials included in the ICECAP analysis were postop

 

[evilbooyaa]

I disagree that MFS predicts survival in the postoperative setting. Happy to be corrected but my understanding is that none of the trials included in the ICECAP analysis were postop

Fair point and I may have overstepped the data. If others have time and can investigate this I'd be appreciative.

*EDIT* - I have moved this to its own thread given the fact that I have committed sufficient time and effort to an informative-style post that I want to separate it from the Rad Onc Twitter megathread.

 

[DoctwoB]

If there is actually a MFS benefit of adjuvant RT compared to not adjuvant (forget whether it's salvage vs not receiving RT at all), then yes, adjuvant therapy is warranted in anyone who is at signficant risk of being lost to follow-up.

This is why we still recommend adjuvant RT or chemo for stage I seminoma who is not going to do surveillance properly.

We 'over-treat' the vast majority of patients who get adjuvant therapy to improve local recurrence, QOL, all sorts of endpoints that aren't overall survival in lots of clinical scenarios outside of prostate cancer. Metastasis-free survival in prostate cancer is a predictor of overall survival.

Combine this with the fact that people are extrapolating RADICALS/RAVES to Gleason 9+ disease patients (when most of these patients were Gleason 7) and I think there needs to be some serious questions about adjuvant RT.

You are looking at prostate cancer in a vaccuum, not realizing (through no fault of your own) that adjuvant therapy with radiation (across all cancers) has pretty much always worked exactly the way you are describing (and feeling discomfort with).

The unique issue with prostate cancer is that there is a toxicity of surgery (urinary incontinence) can persist for upwards of 3-6 months until peak recovery, which is such an extreme outlier compared to other post-surgical situations where we are routinely delivering radiation therapy. And then there's a concern that delivering radiation will 'stop' recovery of that toxicity.

The key phrase there is "anyone who is at significant risk of being lost to follow up"

There is ample evidence that as docs we are horrible at predicting who will and won't be compliant with our treatment recommendations. As such, if we base major treatment decisions on that assessment, we are doing a disservice to a lot of patients, as well as introducing sticky ethics of application of our own implicit bias in assessing likely adherence.

FWIW I do agree with some of your concerns, that a GG2 pT3a negative margins is a very different patient from pT3b GG5 with extensive margin. Adjuvant vs. salvage in the latter patient is mostly academic, as they will almost certainly need xrt it's just a matter of time. I still will await post-operative PSA and delay treatment if undetectable. If PSA persistent it's considered adjuvant anyways. If undetectable, then i'll buy time with watching the psa until detectable, and then depending on how they are recovering start ADT and wait a bit longer.



[1] Wagner JH, Justice AC, Chesney M, Sinclair G, Weissman S, Rodriguez-Barradas M, VACA 3 Project Team Patient- and provider reported adherence: toward a clinically useful approach to measuring antiretroviral adherence. J Clin Epidemiol. 2001;54:S91–8. [PubMed] [Google Scholar]
[2] Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians’ ability to predict patients’ adherence to antihypertensive medication in primary care. Hypertens Research. 2008;31:1765–71. [PubMed] [Google Scholar]
[3] Morton A, Riddle R, Buchanan R, Katz D, Birch J. Accuracy in the prediction and estimation of adherence to bracewear before and during treatment of adolescent idiopathic scoliosis. J Pediatr Orthopaedics. 2008;28:336–41. [PubMed] [Google Scholar]
[4] Parker CS, Chen Z, Price M, Gross R, Metlay JP, Christie JD, Brensinger CM, Newcomb CW, Samaha FF, Kimmel SE. Adherence to Warfarin assessed by electronic pill caps, clinician assessment, and patient reports: Results from the IN-RANGE Study. J Gen Intern Med. 2007;22:1254–59. [PMC free article] [PubMed] [Google Scholar]
[5] Turner BJ, Hecht FM. Improving on a coin toss to predict patient adherence to medications. Ann Intern Med. 2001;134:1004–06. [PubMed] [Google Scholar]

 

[Chartreuse Wombat]

Fair point and I may have overstepped the data. If others have time and can investigate this I'd be appreciative.

*EDIT* - I have moved this to its own thread given the fact that I have committed sufficient time and effort to an informative-style post that I want to separate it from the Rad Onc Twitter megathread.

I have overstepped as well, sort of. According to the data supplement from the ICECAP study two trials of adjuvant XRT (SWOG and ARO) included (n=800) of the more than 12,700 patients included. I believe Dan Spratt has a twitter post on this but I don't have an account on X

 

[evilbooyaa]

The key phrase there is "anyone who is at significant risk of being lost to follow up"

There is ample evidence that as docs we are horrible at predicting who will and won't be compliant with our treatment recommendations. As such, if we base major treatment decisions on that assessment, we are doing a disservice to a lot of patients, as well as introducing sticky ethics of application of our own implicit bias in assessing likely adherence.

FWIW I do agree with some of your concerns, that a GG2 pT3a negative margins is a very different patient from pT3b GG5 with extensive margin. Adjuvant vs. salvage in the latter patient is mostly academic, as they will almost certainly need xrt it's just a matter of time. I still will await post-operative PSA and delay treatment if undetectable. If PSA persistent it's considered adjuvant anyways. If undetectable, then i'll buy time with watching the psa until detectable, and then depending on how they are recovering start ADT and wait a bit longer.



[1] Wagner JH, Justice AC, Chesney M, Sinclair G, Weissman S, Rodriguez-Barradas M, VACA 3 Project Team Patient- and provider reported adherence: toward a clinically useful approach to measuring antiretroviral adherence. J Clin Epidemiol. 2001;54:S91–8. [PubMed] [Google Scholar]
[2] Zeller A, Taegtmeyer A, Martina B, Battegay E, Tschudi P. Physicians’ ability to predict patients’ adherence to antihypertensive medication in primary care. Hypertens Research. 2008;31:1765–71. [PubMed] [Google Scholar]
[3] Morton A, Riddle R, Buchanan R, Katz D, Birch J. Accuracy in the prediction and estimation of adherence to bracewear before and during treatment of adolescent idiopathic scoliosis. J Pediatr Orthopaedics. 2008;28:336–41. [PubMed] [Google Scholar]
[4] Parker CS, Chen Z, Price M, Gross R, Metlay JP, Christie JD, Brensinger CM, Newcomb CW, Samaha FF, Kimmel SE. Adherence to Warfarin assessed by electronic pill caps, clinician assessment, and patient reports: Results from the IN-RANGE Study. J Gen Intern Med. 2007;22:1254–59. [PMC free article] [PubMed] [Google Scholar]
[5] Turner BJ, Hecht FM. Improving on a coin toss to predict patient adherence to medications. Ann Intern Med. 2001;134:1004–06. [PubMed] [Google Scholar]

I hear you on the first line. Unfortunately a per-protocol analysis is going to be fraught with its own confounding.
It's a tough line to walk. I think most prostate cancer patients are likely to be fine waiting for salvage. And the utility of salvage RT (as opposed to palliative hormonal therapy) is slowly being drilled into Urologists's heads.

But, ~25% of patients from the recent EMBARK trial (https://www.nejm.org/doi/full/10.1056/NEJMoa2303974) underwent prostatectomy, had PSA > 1, no distant mets (albeit on CT/Bone scan) and still ended up not getting salvage RT. And this is a recent trial spearheaded by Urologists. I can't blame the patients on that stat. Only those willing to enroll a patient s/p prostatectomy, without metastatic disease, to a trial without the patient having attempted salvage radiation first.

In regards to bolded - although trials may have called it so, PSA being persistently detectable is, by definition, salvage therapy.

Not all patients who have detectable PSA require ADT. There are significant variations in practice nationwide but I use a PSA threshold of 0.5 - 0.7 before I even entertain idea of ADT in a N0 patient.