Post-prostatectomy Management of Prostate Cancer

hi and welcome to Raton talks a lecture series designed for students and residents of radiation oncology my name is Ria I am currently a pgy5 resident at the University of Pittsburgh and today we will be continuing in our prostate cancer series with a discussion on the management of prostate cancer in the postoperative setting so post prostatectomy in our previous talks uh we really discussed management of prostate cancer with definitive radiation therapy and we also discussed um adding Androgen deprivation therapy along with the radiation for patients that have unfavorable intermediate risk disease or higher now not

all patients will opt for definitive radiother theapy for managing their prostate cancer a lot of them might opt for prostatectomy as their definitive treatment when do we need to intervene with radiation as well as possibly Androgen deprivation therapy in the post prostatectomy setting as we will learn uh shortly here uh we really think about adding radiation when patients have surgery for localized prostate cancer and then show signs of biochemical progression um and so in this talk we're going to start by defining biochemical progression in the post prostectomy setting um and then we're going to get

into some of the trials that guide our Management in this space so let's start by defining what is actually considered a biochemical recurrence or biochemical progression the definition of this really depends on if we're talking about the post radiation setting or in the post prostatectomy setting so I think in the surgery setting it's a little bit more straightforward after the prostate gland and seminal vesicles are removed um the PSA for our patients should be undetectable right because the prostate is now gone so the PSA should be undetectable there are different definitions of biochemical recurrence after

surgery so the AA definition of biochemical recurrence is a PSA that is greater than2 nanog per milliliter on two consecutive readings also accepted especially in the era um the modern era where we now have Ultra sensitive PSAs uh two consecutive Rises of PSA greater than 0.1 nanogram per milliliter is also considered a definition of biochemical recurrence so the big takeaway here is that after prostatectomy we expect that PSA to become undetectable and then um the biochemical recurrence is defined as either a PSA greater than 0 2 or two consecutive Rises of the PSA with a

value greater than 0.1 in the post radiation setting the post radiation PSA does not always become undetectable what we do expect is that it should drop and it should eventually hit its lowest point or its nater and we really establish that by closely following up these patients and checking their PSA every few months initially it'll drop after after the radiation it might drop some more and then at some point it will hit its lowest value and then it might start to rise again but a broadly defin a broadly accepted definition of a biochemical recurrence is

defined by the Phoenix criteria of biochemical recurrence so the Phoenix criteria says that a PSA rise of greater than 2.0 nanog per milliliter over the nater um so nater plus 2 or more is considered a biochemical recurrence and so if a patient's PSA is let's say it's seven before treatment and then it drops to six and then it drops to four and then it drops to three and that's kind of its Nat and then it becomes 3.1 3.2 it's reached its nator and it's kind of rising but we're really not worried about a recurrence at

these low values if the PSA jumps from that nater of three to a value of five however so two points above the nater that is when we consider it a biochemical recurrence after radiation now of course we can't just keep a you know we can't just get caught up in the Phoenix definition and rely purely on that we also really care about the PSA doubling time and the PSA velocity all things that we initially talked about in our overview um but these are some of the most broadly accepted definitions of a biochemical recurrence after either

prostectomy or radiotherapy and I think the big takeaway here is that after prostate we routinely expect that that PSA should become undetectable and if it remains detectable after surgery that tells us that the disease was not completely eradicated on the other hand after radiation even if it doesn't ever become undetectable that doesn't mean that the radiation did not completely take care of the disease so two different definitions depending on what therapy they got so I think those definitions are important to understand and it's important to realize that after surgery we expect that patients PSA will

become undetectable now historically we had data that suggested that for patients who had surgery who then had certain risk factors at the time of surgery so things like positive margins or T3 disease meaning they had either extracapsular extension or seminal vesical Invasion um these risk factors uh were obviously higher risk factors and we should probably offer adant radio the therapy to those patients that was based on older studies and they showed a benefit to the biochemical progression free survival um just offering adant radiation across the board for anyone with certain risk factors in the modern

era um what we have learned based on more updated trials is that we don't necessarily need to offer adant radiation to all of these patients what we can do is monitor their PSA after surgery even if they have these risk factors and if their PSA remains undetectable and they don't have a biochemical recurrence then that tells us that we have eradicated their disease with surgery alone however if that PSA never becomes undetectable or if the PSA becomes undetectable and then starts to rise again um at some point later then they're telling us that they still

have disease that we need to address and that is really when we intervene with radiation so what we practice in the modern era we actually call that a salvage radiation approach but historically we were offering adant radiation to any patients with high-risk disease so let's start by talking about those historical trials and then we'll talk about the the more modern trials that support Salvage radiation so here are some historical studies that probably are not super applicable for our practice in the modern era but they are important to be aware of for a historical perspective as

well as for boarding exams so swag 8794 eortc 22911 and then the arrow 9602 study so all of these studies took patients that were status post radical prostectomy and either had a positive surgical margin or T3 n0 disease so either extracapsular extension or seminal vesicle Invasion which is the definition of pathologic T3 disease now the swag study and the EC studied uh really allowed for patients with any PSA value um the arrow study however specified that the PSA had to be undetectable so less than 0.1 nanograms per milliliter which means undetectable um only the arrow

studies specified that patients truly had to have an undetectable PSA after having that surgery the swag and the EC studies did not specify that which means theoretically if the PSA was detected able it wasn't really you know you were already doing Salvage at that point it wasn't really true adant um but anyway these were the three studies they took patients with positive uh surgical margins or T3 disease and then they randomized them to either observation or radiation around 60 gray in 30 fractions to the prostate faosa um and they so they were randomized to Observation

versus radiotherapy um alone and in the swag study no ADT was allowed the 10-year results of all of these studies showed that there was an improvement in the biochemical progression free survival with the addition of radiation so the biochemical progression free survival went from somewhere around 30 to 35% with observation up to around 60% with radiation so the Improvement in biochemical progression free survival almost almost doubled the EC study um and the arrow study did not show any benefit to the survival but the swag study actually showed around a 10% Improvement in survival as well

um so the survival went from 66% with observation up to 74% with um the radiation so all three studies showed Improvement in biochemical progression free survival but only the swag study showed an overall survival benefit and they also showed an improvement in um distant metastasis free survival So based on these trials again all patients were post-operative after radical prostectomy and they had either positive surgical margins or pathologic T3 disease so invading things right either extracapsular Invasion or seminal vesicle Invasion and they were randomized to Observation versus adant radiation and agant radiation improved biochemical um progression-free

survival from around 30% without without any intervention up to 60% with radiotherapy and then again only the swag study showed an improvement in overall survival and distant metastasis free survival and So based on these older studies the standard of care historically was to just routinely offer adant radiotherapy for anyone with those highrisk factors so positive surgical margin or T3 disease but then somewhere along the way we ask the question we'll do all of these men truly need adant radiotherapy can we kind of monitor them with a PSA and if their PSA stays undetectable after surgery

um maybe they don't actually have any residual disease or recurrent disease and maybe we can continue to watch them um but if their PSA becomes undetectable and then starts to rise again which tells us they're having a biochemical recurrence maybe we only intervene with radiation at that point and that is called an early Salvage approach and um there were a series of trials that we'll talk about that investigated exactly that and what they found is that treating with early Salvage radiation so only treating with radiation if they have evidence of biochemical recurrence um versus adant

meaning everybody gets post-operative radiation if they have those risk factors um what they found is that the early Salvage radiation actually works it does not uh sacrifice any of the cancer outcomes in these patients and it actually spares around 50% of patients from having to undergo post-operative radiation so you're sparing them um all of the you know morbidity of having to go post-operative radiation um and so that is really what we practice now in the modern era is this early Salvage approach where we monitor their PSA post prostatectomy we look for evidence of a biochemical

recurrence if that PSA becomes undetectable and only then do we intervene um with early Salvage radiation if they have biochemical recurrence so here are the three Salvage radiotherapy trials that randomize patients to adant versus early Salvage radiation and you know those swag eortc and arrow studies are definitely important for historical perspective and they're important to know for boards but Raves radicals and Jou AFU 17 I would say are the three most important trials for us to know um in the post prostatectomy setting that guide our management to salvage radiotherapy so all three of these trials

as that exact question that we talked about instead of adant radiation can we just watch their PSA and only come in with early Salvage radiation if it starts to rise again um and so all three trials took patients who had undergone radical prostectomy and had either positive surgical margins or T3 disease or higher and they all had to have a low post-operative PSA so in Raves and Jou that posttop PSA was less than1 in radicals it was less than. 2 they then took those patients and either randomized them to adant radiation or early Salvage radiation

and how did they approach early Salvage radiation well they had a threshold for who needs to get radiation so in Raves and in Jou the Salvage threshold was a PSA of. 2 in radicals it was a PSA of 0.1 and Rising for two consecutive values or any consecutive PSA Rises times three so basically a biochemical recurrence right so if patients had a biochemical recurrence they then went on to receive Salvage radiation either to the prostate fossa alone as in Raves or um whole pelvic radio therapy was optional for the radicals and Jou and then Jou

also gave everyone 6 months of Androgen deprivation therapy um radicals actually had a separate arm uh which we will talk about um later in this talk um called radicals HD where they randomize them to various um intervals of Androgen deprivation therapy so zero months or 6 months or 24 months um so we'll talk about that later but the bottom line is after a biochemical recurrence and the Salvage arm um they got radiation at least to the prostate fossa and some of the trials allowed whole pelvis radiation and androgen deprivation therapy as well at 5 years

they found no significant difference in biochemical progression free survival in any of the trials between the Salvage arm and the adant arm so in Raves and radicals the biochemical progression free survival was in the mid 80s somewhere around 86 to 88% in Jou remember where everyone got about 6 months of ADT um the event free survival was around 90 to 92% and none of these were statistically significantly different um and so the Salvage approach was considered non-inferior the other thing I want to point out is in the Salvage arm so so in the agant arm

right obviously everyone had to get radiation how many patients that were followed in the Salvage arm actually met the criteria for biochemical recurrence and went on to receive the intervention it turned turns out that it was around 50% of patients um so in Raves it was 50% in radicals it was 32% and in jatu gfu it was 54% um and so around 50% of the patients actually needed Salvage radiation and the rest of them were just continued to be observed because their PSA never actually became detectable again and so these trials tell us that there's

no significant difference in the biochemical progression free survival or event free survival with a salvage approach compared to an adant approach and actually with the Salvage approach we can spare around half of our patients from needing post-operative radiation and so um there was also a meta analysis called the artistic metaanalysis and these results were confirmed so in the artistic meta analysis 39% of patients actually needed Salvage radiation so they were actually able to spare around 60% total from needing any um radiation postoperatively and then the event free survival was around 88 to 89% in both

arms um and no significant difference so we have the Raves radicals and Jou trials as well as the artistic metaanalysis that combined all three of these trials and told us that there's no significant difference in biochemical progression free survival or event free survival with Salvage versus adant radiation and with the Salvage approach when we actually monitor their PSA wait for a biochemical recurrence and only if they have that do we intervene with radiation that approach spares around 50% of men from needing radiation so just to summarize everything that we've talked about to this point historically

patients with particular risk factors so a positive surgical margin or T3 disease so extracapsular extension or seminal vesicle invasion um historically we had data that showed us that if these risk factors existed then adding adant radiation to all of these patients um benefits them in terms of their biochemical progression-free survival however more modern studies the Raves radical and Jou study and then the artistic metaanalysis that combined results of all of those studies showed us that if we actually just do early Salvage radiation rather than across the board adant for everyone if we monitor their PSA

and only intervene if they have biochemical recurrence early Salvage radiation actually has an equivalent biochemical progression-free survival and with that approach we can spare around half of our patients from needing any adant radiotherapy and so that is really what we practice in the modern era after post prostatectomy so even if they have a positive margin even if they have T3 disease so those high risk factors you know all these Pat paat we're going to follow them longterm with PSA values and if their PSA remains undetectable then well and good they don't have any evidence of

disease but if that PSA starts to show signs of biochemical recurrence and remember we talked about the different definitions so either 0.1 and rising or greater than 0. 2 um if if we can show that they have biochemical recurrence then at that point we should offer post-operative radiation at minimum postoperative radiation to the prostate fucil now keep in mind that all of these trials that we talked about Raves radicals and J they first before these patients were enrolled into the study they verified that their PSA was undetectable um prior to enrolling right so Raves and

Jou made sure it was less than 0.1 the radicals trial made sure that it was less than 0 2 some patients after they have surgery might just have an elevated PSA right off the bat on that first PSA value typically in that scenario what we would do is just recheck the PSA in a very short interval and make sure that it remains high and if it does then that tells us that we have not completely eradicated their disease and so in that case we're giving them radiation and um it's really you know it's it's not

even Salvage after a biochemical recurrence they really just require adant radiation because their PSA never uh never became undetectable so now hopefully we have a good understanding of who should we think about radiation to the prostate fossa um after surgery um if they have either their PSA never becomes undetectable after surgery or if they have a biochemical recurrence now the trials that we talked about Raves radicals and Jou they were not completely um you know in uniform in terms of their approach to adding Androgen deprivation therapy and also in their approach to adding pelvic radiation

you know that was really left up to the training physician and so now we're going to go through some studies that kind of help us to understand when we're offering post- prostatectomy radio therapy which patients should we think about adding Androgen deprivation therapy and who should we think about adding pelvic radiother therapy uh when we're treating in the Salvage setting um and so what we'll find is that this is kind of a not a totally black and white area it's definitely a gray area um and a lot of Physicians will kind of tailor um how

they approach this problem based on the patient's risk so taking into account their not just their PSA but also their t-stage their gleon score um and in the modern era we also sometimes will try to incorporate their genomic risk factors um so kind of that decipher genomic risk score and when we do give Androgen deprivation therapy the duration can be up to two years um everyone is wary of two years of Androgen deprivation therapy of course because it's not without side effects um but we'll find that some patients really benefit from it um and and

it has shown benefit um so let's go through some of these trials and try to kind of outline the evidence here the first trial that we'll talk about is rtog 9601 that took patients after surgery and they had radical prostectomy and lymph node dissection and they had a PSA of 2 to4 and they were randomized to either Salvage radiother therapy with placebo for 2 years or Salvage radiotherapy with ADT uh 150 mg of bicalutamide daily for 2 years the radiation that they received um was 64.8 gray in 36 fractions to their prostate bed so 1.8

gray per fraction and they did not treat the pelvic nodes all of these patients had um negative lymph node dissections so they were node negative and these patients were like we said randomized to radiation to the prostate fossil alone or um um ADT and in you know if they weren't getting ADT they were taking Placebo pills for 2 years the compliance with um the placebo or the ADT pills was around 70% in all the patients at around 2 years and what they found is that with two years of Androgen deprivation therapy overall survival prostate cancer

specific survival um distant metastasis and biochemical progression free survival were all significantly improved with the addition of ADT so there was about a 5% Improvement in overall survival um 76% with ADT versus 71% with Placebo prostate cancer mortality was cut in half so 6% with ADT versus 133% with Placebo um there was about a 10% Improvement in distant metastasis rates so 15% rate of dm with ADT um up to 23% with the placebo and then the second biochemical failure rates were also significantly low or 40% with ADT up to 68% with Placebo and so radiation

plus 2 years of ADT significantly improved overall survival prostate cancer specific survival distant metastasis free survival and biochemical progression free survival the big toxicity with bicalutamide for 2 years was gynacomastia um you know there's also you know cardiac toxicity and um hepatotoxicity and things like that but the big toxicity with taking big glutamide every day 70% of those patients had gynacomastia versus only 11% in the placebo arm um and so you know we typically don't prescribe bicalutamide alone if we're doing long-term Androgen deprivation therapy we'll often opt for an lhrh Agonist like lolide or goserelin

and bicalutamide we often just use as a bridging therapy to that lhrh Agonist but bottom line rtog 9601 2 years of ADT in the Salvage radiation setting significantly improved many outcomes including overall survival um and and so this was uh the outcome of 9601 there was a secondary analysis of rtog 9601 that was published and the big takeaway from this secondary analysis is that the overall survival benefit for two years of Androgen deprivation therapy was really seen in patients that had a PSA that was greater than six um so 6 is a very important number

to remember for 9601 um and that's sort of the cut off for patients that had a PSA of 6 or less they not only saw that there was no significant survival benefit but they also saw that there was increased other cause mortality um higher risk of grade three to five cardiac events um and so the secondary analysis of 9601 tells us that there's improved survival with 2 years of ADT for patients with a PSA that's greater than 6 and it really does not improve um if we add ADT for patients with a PSA of less

than 6 and in fact adding that much ADT can actually increase our other cause mortality um so we do need to be careful about who we are putting on two years of Androgen deprivation therapy it's certainly not without uh side effects Jou AFU 16 is another study um that looked at South AG radiation with or without Androgen deprivation therapy um and you know very similar to 9601 they took node negative patients who had undergone surgery and initially had an undetectable post-operative PSA and then it started to Rise um these patients were randomized to post-operative radiation

alone and they only added pelvic radiation if the patients did not have a nodal dissection versus post-operative radiation 66 gra 33 fractions Plus 6 months of Androgen deprivation therapy and in this trial the ADT was a goserelin injection so that is an lhrh Agonist jhatu AFU 16 showed that the 10-year biochemical progression-free survival and distant metastasis-free survival significantly improved with 6 months of Androgen deprivation therapy plus radiotherapy in this trial importantly they defined biochemical failure as an incre increase in the PSA concentration by 0.5 from the nater so different than the Phoenix definition that we

talked about previously um but the biochemical progression free survival with um ADT went from 64% um with ADT and radiation down to 49% with radiation alone so there was a significant improvement with 6 months of ADT the distant metastasis free survival also improved by around 6% so 75% with ADT versus 69% without and there was no change in survival they did a post Hawk subgroup analysis um for the benefit of biochemical progression free survival based on risk and they found that it improved in both the lowrisk and the high-risk subgroup and on their initial publication

they actually suggested that there was a greater magnitude of benefit to the addition of Androgen deprivation in patients with a PSA greater than 0.5 um and they found no significant differences in toxicity or quality of life between groups So based on Jou fu6 um the trial suggested that Salvage radiation with short-term Androgen deprivation so 6 months also improves biochemical progression free survival compared to salvage alone now the radicals trial remember we talked about radicals RT which was one of the Salvage radiation trials they also had another randomization and the patients that were included included in

the randomization for hormone therapy were included in radicals HD and just this year they published um two different analyses from radicals HD there was a zero months versus 6 months and then there was a 6 months versus 24 months um so we're going to start by talking about the zero months versus 6 months um publication so in radicals hd0 versus 6 months they included patients uh 1,400 patients with prom prominently intermediate risk prostate cancer and they had patients that were treated with both um agant radiation as well as Salvage radiation and these patients were randomized

to either no Androgen deprivation therapy or 6 months of Androgen deprivation and they had different options as to what they could get for Androgen deprivation therapy they found that there was no significant difference in their primary endpoint of distant metastasis free survival with Z months versus uh 6 months of Androgen deprivation again in a predominantly intermediate risk group so the distant metastasis free survival was just around 80% in both arms um at 10 years with no significant difference they had a secondary endpoint of clinical progression-free survival and time to salvage Androgen deprivation therapy and that

did show a significant benefit with short-term Androgen deprivation so the hazard ratio is around 0.5 for both um outcomes so the clinical progression free survival as well as the time to salvage Androgen deprivation but their primary endpoint of distant metastasis free survival was not significantly um improved and again remember the patients on radicals HD were predominantly intermediate risk the other publication was uh 6 months versus 24 months Androgen deprivation therapy and um this was the other publication from radicals h they had around 1500 patients on this publication and these patients were predominantly high risk so

they had glein score of 8 to10 um t3a or higher disease prostate cancer and once again they included patients with both agiven as well as Salvage radiation they were randomized to radiation for 6 months versus radiation for or sorry radiation and six months of Androgen deprivation therapy not radiation for 6 months but radiation plus 6 months of Androgen deprivation or radiation plus 24 months of Androgen deprivation and in this trial the distant metastasis free survival actually did improve significantly with the long-term Androgen deprivation there was a 6% Improvement in 10year uh distant metastasis free survival

so 72% with short-term versus 78% with long-term Androgen deprivation and you can see the kapan Meer curve starting to separate it's not a huge separation but it's a 6% separation at 10 10 years again the downside of long-term Androgen deprivation is a longer duration of Adverse Events and they did do an analysis and the there did not seem to be any interaction between the benefit of Androgen deprivation and PSA levels so for a trial that looked at predominantly high-risk patients long-term Androgen deprivation versus short-term actually seem to improve the metastasis free survival um 78% versus

7 2% again at the cost of a longer duration of side effects from hormonal therapy the last study I want to mention before we sort of take a step back and try to synthesize all this data is the sport trial also called r534 that not only um looked at adding short-term Androgen deprivation therapy but also looked at potentially adding pelvic lymph node uh radiotherapy so this trial also took patients with prostate cancer they had to have pt2 to3 disease a glein score less than or equal to 9 and they underwent surgery and had an initially

undetectable PSA That Was Then Rising somewhere between 0.1 to two so a true definition of Salvage radiotherapy and they were randomized to either radiotherapy to the prostate bed alone so 64.8 to 70.2 gray at 1.8 gray per fraction prostate bed radiotherapy Plus shortterm Androgen deprivation with four to 6 months um of ADT or prostate bed radiotherapy with pelvic lymph node radiation as well with short-term Androgen deprivation therapy so for the um radiotherapy they did 45 gray to the pelvis and then they did a sequential boost um so kind of cone down uh to just treat

the prostate bed to a higher dose of 64.8 to 72 70.2 Gray um and all these patients got short-term ADT in this arm so the fiveyear results of the study actually show that there was improved biochemical progression free survival and distant metastasis free survival but not overall survival with um that last arm of prostate radiation plus pelvic lymph node radiation plus short-term Androgen deprivation therapy so the 5year um biochemical progression free survival was 87% in that third arm um and then it was 71% in prostate bed alone 81% in prostate bed plus short-term radiation or

I'm sorry short-term Androgen deprivation um and then it was all the way up to 87% with all three of those interventions and again for biochemical progression free survival they used the Phoenix definition the rates of 5-year um distant metastasis were also significantly improved in that third arm with only 5% and then the 5-year overall survival was the same around 95% in all arms they did a subset analysis and found that the benefit to adding pelvic lymph node radiation um to prostate bed radiotherapy and short-term Androgen deprivation was really there for patients with a PSA greater

than. 35 um and then in terms of toxicity they did see worse acute and late toxicity in Arms 2 and three mostly um hematologic toxicity um and they saw significantly worse rates of both acute as well as late um grade 2 or Worse hologic toxicity so the conclusion from the rtoo 534 or sport trial was that Salvage radiation with um pelvic radiotherapy to 45 gray and then short-term Androgen deprivation for four to 6 months significantly improves biochemical progression free survival and distant metastasis free survival without an improvement in overall survival and although the study was

not powered for this specific subgroup analysis it did seem like there was a benefit for patients with a PSA greater than 35 um and this was a short five-year followup um we definitely need to follow these patients for longer and get that longer term follow up so at this point um my head is certainly spinning and yours might be too um because how do we make heads of heads or taals of this data right um I have so many questions how long should we be giving and Esten deprivation therapy 6 months 24 months should all

of our patients be getting pelvic noal or radiation or should we use that cut point of 035 as per the sport analysis I think in reality um you will find that this is often a very individualized decision and practice patterns definitely vary depending on who you talked to um kind of what how they interpret this data I think this data can be interpreted in a lot of different ways many Physicians I think are wary of the side effects of 2 years of Androgen deprivation therapy um and so we don't take this decision lightly and and

we really try to consider the the patient as a whole um obviously what they can tolerate and and what they've already been through and then we think about the risk factors of their disease so things like their glein score their t-stage their pre-treatment PSA as well as their PSA Trend um and then we also can try to use genomic classifiers to to try to help risk stratify so if you recall I think we've talked about the decipher genomic risk classifier before um but it basically gives us a score on a scale of 0 to one

based on 22 different genes um and it helps us to think about the patients uh risk of of biochemical progression and and distant metastasis so um there was actually a prospectively designed validation study for the decipher genomic u classifier in the patients that were in r96 601 and in this paper um you know the the decipher score significantly correlated with oncologic outcomes when it was established or when it was examined both as a continuous as well as a categorical variable and so it has been kind of validated as a prognostic marker for biochemical progression free

survival distant metastasis free survival and overall survival and then NRG g006 is a phase 2 study that is now closed to AC cruel and we're waiting on its results but it randomized patients um to salvage radiation with or without apalutamide um based on the decipher genomic risk score um so you know I think some practitioners may be using decipher genomic classifier to help guide their decisions um and currently it has not been validated as a predictive tool to help us predict response to therapy um but it certainly is something that that is developing and and

we're pending the results of nrggg 006 um but you know I think we are at a point where genomic risk classifiers are definitely on their way to becoming predictive tools and and helping us to risk stratified treatment for our patients based on that genomic risk score also recently published uh were guidelines um from Astro AUA and suo and they it's a three-part um public a um for management of uh Salvage radiation in the biochemically recurrent setting for prostate cancer and they talk about indications for adding Androgen deprivation to salvage radiotherapy in part two of their

um three-part consensus guideline so their indications include things like grade group four to five disease stage pt3b to four disease um surgical margin status node positive disease short PSA doubling time um a short interval from that Primary Therapy to PSA recurrence a higher post- prostectomy PSA as well as a genomic uh classifier risk and imaging findings on pet um so I think these guidelines can certainly help us um you know they were published before the radicals HD data so they did not really comment on the duration of hormonal therapy um but you know I think

these guidelines are also helpful to fall back on if we're ever unsure genomic risk classifier is mentioned in these guidelines and that can be helpful as well um they did raise a point about surgical margin status I think this is really interesting to note so if patients do have positive surgical margins um as you can probably imagine they are at increased risk of recurrence however um they're also at a lower risk of progression after undergoing Salvage radiotherapy and when I was doing Raton questions I actually got a question on this and it makes sense if

you think about it why they might be at a lower risk of progression after Salvage radiation because if we're giving them Salvage radiation for a rising um PSA in the postsurgery setting and they actually have a surgical margin that was positive then we're more likely to treat the disease with radiation because it's probably in the prostate fossa right if they do have a positive surgical margin so that's actually kind of a good thing in a way because it tells us that there's probably a lower risk of progression after Salvage radiation um so just wanted to

make that point about positive surgical margins um and then also kind of just keep in mind that these are various indications for adding ADT to salvage radiotherapy so moving on now um so far we have talked about Salvage radiation so you know when the PSA is undetectable um after surgery and then they later have evidence of biochemical recurrence based on those various criteria that we talked about there are certain patients however that we would actually just give adant radiotherapy where after surgery if certain features are present then we we just go ahead and give them

all adant radiotherapy now we already talked about one of those indications where you know if that PSA never becomes undetectable after surgery right that is a situation where they've kind of declared themselves that they still have residual disease somewhere and so they would probably benefit from postoperative radiation the other situation is if they have pathologic node positive disease uh we'll talk about some studies that we have but they basically tell us that there's an all-cause mortality benefit with adant radiation um versus Salvage for patients with pathologic node positive disease now keep in mind that if

we know upfront that patients have node positive disease remember node positive disease is considered stage four a for prostate cancer um and we we talked about this previously in this series but there's not great data but typically I think the just Sal is to manage these patients with radiotherapy because they're higher risk and if they are already node positive then we feel like we don't have a great chance of getting that PSA to be undetectable after surgery however um sometimes patients will clinically not have any evidence of nodes and then at the time of surgery

we will find that they actually had pathologic node positivity and that's why lymph node dissection is so important um so let's talk about some of the data that we have in this space of course this is not um this is a pretty challenging situation and we don't have a lot of or any really randomized data um to guide our decisionmaking but we do have a couple of retrospective studies um so the first retrospective study I'll share is from Abdullah adol um that was published in 2014 and it was a retrospective study of 1100 patients who

had um radical prostatectomy and pelvic lymph node dissection with pn1 disease and they performed a regression tree analysis so all these patients were treated with um Androgen deprivation therapy adant with or without adant radiotherapy and if they did receive adant radiotherapy um most of them were treated to both the prostate fossa as well as the pelvis within 90 days and what they found based on the regression tree analysis is that there were two specific spefic groups that actually seem to derive um a case specific mortality benefit so those were patients that had either one to

two nodes with a glein score of 7 to 10 and um t3b to four disease or positive surgical margins the other group that seemed to derive a benefit were patients that had three to four nodes if you look at the the table and kind of how this regression tree was was designed um the the group that's highlighted in the red box so the patients that we just talked about one to two nodes with a glein score of 7 to 10 and pathologic t3b to4 disease or positive surgical margins and then three to four nodes kind

of fall in that medium range there are certain lower risk patients um with a glein score of 7 to 10 and negative surgical margins or T2 to t3a disease and also even lower so glein score of 2 to six that don't seem to derive a benefit and then there's also higher risk patients with greater than four positive nodes that don't seem to derive any benefit so really here there's kind of seems to be a medium range where intervening with post-operative radiation does seem to help the more recent data that we have in this space is

by first author tilky adol and they performed a retrospective study of patient with pt2 to T4 disease and pathologic N1 prostate cancer who underwent radical prostatectomy and then they looked at patients that were treated with no radiation versus Salvage radiation versus adant radiation and um they stratified patients based on the number of lymph nodes that were positive so 1 to three versus four or more what they found is that agant radiotherapy significantly decreased the all cause mortality risk compared to Salvage radiation in the entire cohort so adant radiation provided an 8% Improvement in all cause

mortality um with each additional lymph node that was positive so when they looked at all cause mortality for patients with greater than or equal to four nodes the all cause mortality went from 8% um with Salvage radiation up to or down I'm sorry 8% with Salvage radiation up to 23% with adant radiotherapy and that was statistically significant so higher all cause mortality with adant compared to salvage in the group with just one to three nodes there was not a statistical significance there so the all cause mortality went from 133% with Salvage up to 14% with

adant radiotherapy however um what they found is that they estimated around a 3% benefit in all cause mortality for um the sub group that was 1 to three nodes and so you would actually need a very large sample size to show this and so perhaps the study was just underpowered to show an a significant Improvement in all cause mortality um and so the conclusion from this trial was that adant radiotherapy improves all cause mortality in patients with pn1 prostate cancer and for each additional lymph node there's around an 8% Improvement in all cause mortality so

again I think the textbook answer is that for pathologic node positive disease we do try to offer adant radiation rather than early Salvage um as we do for patients with positive surgical margin or T3 to T4 disease um but again uh in practice you will see individualized decision making um based on the patient the last section that I'll mention here uh before we conclude is um a trial that looked at dose escalation in post-operative um radio therapy and uh did not find a benefit so Sac 09/10 um was a randomized trial that looked at dose

escalated Salvage radiotherapy um so they randomized patients undergoing Salvage radiation to either 64 gray conventionally fractionated radiation um versus 70 gray of dose escalated radiotherapy and they found no significant Improvement in the biochemical progression free survival with dose escalation so the six-year biochemical progression free survival was just around 61 to 62% in both arms what they did see was that there was significantly worse grade 2 or Worse GI toxicity with um 70 gray as compared to 64 gray so the late rates of grade two or Worse GI toxicity were 20% with 70 gray versus 7%

um with 64 gray and that was significant so no significant benefit to dose escalation for the process at fossa and so typically we we don't utilize that we typically just treat um to around 64 gray when we're treating the prostate fossa um the only time that I've seen actual kind of dose escalation is if you know we get a psma pet scan in that postoperative setting and there's gross residual disease if you're boosting gross residual disease then um I think people would typically take that to a higher dose um but if if you're not boosting

any gross residual disease then we're not routinely dose escalating for the prostate fossa one other thing I want to mention I don't have a trial on or sorry a slide on this um there was a trial NRG g003 that compared conventional fractionation um to a moderately hypo fractionated regimen they used 62.5 gra 25 fractions and they found that hypo fractionation was non inferior um but they did see numerically higher grade three or Worse GI and gu toxicities in the hypo fractionated arm and they saw some worse acute bowel um symptoms too with hypo fractionation so

there is data for hypo fractionation seems like it's non inferior but may have worse toxicity so big takeaways um from the last couple of sections that we just talked about um we first looked at some retrospective data um for agant radiation for um pathologic node positive disease and we saw that there is probably an a mortality benefit to adant radiation for pathologic node positive disease and that tilky study showed around an 8% benefit in all cause mortality um per additional lymph node um and and that's a relative um benefit for sac9 and 10 um we

looked at no benefit to dose escalation so sac9 and 10 compared 64 grade versus 70 grade of the prostate fossa and found no significant benefit to dose escalation and actually worse late uh grade two or worst GI toxicity so we typically would only dose escalate if there's actually gross disease so somewhere on the order of 74 gray like similar to what conventionally we would do for um intact prostate um but only if there's gross residual disease in the prostate fossa that we can clinically see um but if not no benefit to dose escalation so big

takeaways from uh kind of all of the data that we've talked about here um just to kind of Drive some important points home so we started by talking about historical data for adant radiation for patients with either positive surgical margins or T3 disease uh what we found based on more modern studies including the Raves radicals and jitu data as well as um the artistic metaanalysis that combined all three of those studies we found that an early Salvage radiotherapy approach is equivalent to adant radiotherapy in terms of biochemical progression free survival and if we really monitor

that PSA and if it becomes undetectable after surgery and then has a biochemical recurrence in the post prostectomy setting with that early Salvage approach we can actually spare around 50% of patients from needing um post-operative radiotherapy with early Salvage um so that's really the standard um in the modern era is to kind of watch that PSA now if the PSA never becomes undetectable after surgery um then we we think about kind of doing adant radiation we also talked about these questions of Androgen deprivation therapy and pelvic lymph node radio therapy in the post-operative setting um

along with Salvage radiation and um there's data for at least 6 months of Androgen deprivation therapy and we may consider even up to two years um and you know this is a very individualized decision-making process taking into account many different risk factors as we showed in some of the studies you know r96 one showed a benefit for a PSA greater than 6 for um long-term andren deprivation and so we kind of use those risk factors the clinical risk factors as well as um decipher genomic uh classifier to kind of help guide those treatment decisions we

also talked about patients with pathologic node positive disease and that can be another indication for adant rather than Salvage radiotherapy um and then finally we talked about no benefit to dose escalation in the post PR ectomy setting and 64 gray conventionally fractionated is probably sufficient um the only exception to this would be if you have gross residual or recurrent disease that you can clinically see on a scan um then you would consider boosting that to kind of definitive um definitive doses that brings us to an end here um hopefully this was helpful in kind of

consolidating a discussion on management of prostate cancer in the post prostatectomy setting I I think I say this at the end of pretty much every prostate uh lecture but you know this is first of all not all of the data that we could possibly discuss there are lots and lots and lots of papers in the prostate cancer World um so I really try to just include what is most uh Salient and and some of the important trials that I have actually seen um kind of come up in in clinical decision- making for patients um the

other thing that I hope I've emphasized throughout is that you know all of this data um is is kind of a gray area I think and and nothing is black and white in medicine I think there are certain things that are absolutely wrong and certain things that are absolutely right and I think most practitioners fall somewhere in the middle of kind of a normal distribution where you know there is diversity and I think variation in in practice um if you go from one institution to another and even if you look at one physician to another

within an institution I think everybody interprets this data differently and I think at the end of the day everyone is trying to do what is best for their patients and and there's going to be a lot of um heterogeneity just based on patient populations that are different between practices and things like that so um I I just I hope that this data is helpful I hope that um this discussion is helpful to kind of contextualize a lot of different um studies um but again keep in mind that you know in real life people are going

to do things differently based on their own experience and based on their own interpretation of the data um my goal here is really just to kind of point out some of the important trials and and go over some data that might be pertinent um for board exams um so sorry for that long little Spiel at the end but I hope this was helpful and thank you so much for your time