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so post-operative radiation the question really starts with the pathology report which gives us clues as to whether the patient's gonna fail if so where is adjuvant the therapy appropriate and is it just local therapy that's needed or is it is a really a systemic issue obviously the size extent of the cancer of this Gleason grade whether it was organ confined the margin status status of seminal vesicles and lymph nodes all of these are really important to to get an appreciation of so is it really a scenario like this we're more likely this is a distant failure after primary surgery or is it more of a situation like this where in fact there is a reasonable chance that there is a local component in perhaps local only component to this recurrence it this is some very interesting data these are our trusty biopsies in men with a right with a rising PSA after prostatectomy all with negative staging the scans 40 to 50 percent had a positive biopsy of their prostate bed and of course that under it represents the reality because of a sampling error in that scenario when I saw this data I was like wow there really is a good chance of locally persistent disease in that same study of those with a biopsy proven local recurrence two thirds or it had a positive margins that makes sense but a third actually had negative margins at time of prostatectomy and 20% were in fact organ confined or going to find negative margins yet re biopsied in the prostate bed and it was positive if you look at margin status assessed molecularly so the prosthetic fossa in this case was assessed by five biopsies in rt-pcr for prostate-specific membrane antigen the quarter with organ confined disease by H and E had positive molecular margins that's which again I thought was was was quite extraordinary so at the molecular level there is quite a bit of a potential disease left behind so where do these recurrences occur in general they're gonna happen at the annum an estimate excite the bladder neck posterior to the Trigon these are the areas that that we see if we look at MRIs in patients who had indeed a radiographic visible local recurrence that's where we find these recurrent tumors bladder neck retro vesicle and peri anastomotic sites so those have really informed us in radiation oncology in the fields that we use to design and treat the prostate bed these are sort of historic fields now from the RTOG showing that it's really this space this is a retro grade that you reprogram the peak of the that that you reprogram the bladder that space in that area and here's some old films from the 2d era of treatment treatment that shows you the the basically the area that was was treated we've moved on as per yesterday's talk 3d conformal therapy is now very commonly used and in fact in the States I think I'm RT again has taken over here is a disease setting that i think i marty has little to offer i think there's some benefit but it's little compared to the intact prostate setting however it is being used commonly so i showed you this in the last talk when we were talking about can expert radiation oncologists agree on contouring of nodes well here's the question of can they agree on the prostate bed and this one is equally as shocking again case of two cases one expert radiation oncologist drew 23 cc's while another ten times as much same story their total agreement in this case was only seven CCS and again if you merge down a border of the entire area of the prostate bed it was actually a very large volume I have to say when I contour these cases they probably range from 80 to a maximum of 150 CCS in size so this would be you know these sorts of volumes here are likely just too big and so here again are those each color representing a different radiation oncologist contouring the prostate bed this shocking data led again to an RTOG consensus and we thank the RTOG for developing these sorts of atlases especially for trainees and it really told us that the the the boundaries of the prostate bed should be the caudal vas deferens anteriorly the posterior edge of the pubic bone posterior Lee the anterior rectal wall and laterally to the levator Ani including the levator Ani into the medial border of the operator internai muscles and so this is sort of what the prostate bed looks like now you can see here Surgical Clips this is the area of seminal vesicles this is the bladder neck this is down at peri and Astronautics sites and this is what it looks like in in sagittal plane so and here's just another example so I'm just going to very quickly go through these and just give you a feeling because I think it's important for your logic surgeons to understand what we as radiation on cause you're treating it has to make sense to you as well so we're coming from superior to inferior there you can see remnant SVS being contoured tailoring it up to include more of the bladder neck here you can see that post early it's the anterior edge of the rectum laterally it's going to the medial border of the operator internai muscles now going up to the posterior edge of the pubic symphysis bone going down through the bladder neck in the region of the anastomosis here so that's pretty much what we treat and it always looks like either a thumbs up or a toilet seat I guess and so then there was an independent group in Canada that actually looked at trying to develop a consensus as well long story short they included urologist your geologists and others in the design of these fields and so in fact three neurologists delineated the regions at risk Contras were discussed at a tumor board a clinical target volume was proposed by radiation oncologists and the radiologists and then a final planning target volume was developed with everybody's input and indeed interestingly again inferiorly the it started at the top of the penile bulb entirely the edge of the pubic symphysis post your edge of the pubic symphysis bone laterally medial border of the operator and turn nine muscles posterior the rectum it's great I mean these were two independent efforts coming up with the exact same planning or target volume for post-operative radiation so indeed that is and there you go the toilet seat is is what should be we should be contract nowadays so we could however agree on the dose and so the dose is typically these days in the mid mid 60 gray range so this is a survey of 10 or 11 largely American one institution from Australia survey of how do they treat postoperatively so you can see a lot of places are using IMRT the data supporting that is not that strong a lot of places are using IGRT image guidance remember other things I discussed which I include the e/m transponders those beacons those GPS devices in the post-operative setting as well as daily comb beam and other means you can see that mostly they would agree on those roughly the mid 60 gray range at this snapshot of a number of institutions and that was in the adjuvant setting that was adjuvant dose what about the Salvage setting with a detectable PSA typically most institutions we're adding a fraction or two of radiation in the salvage setting what about regional lymph nodes in the adjuvant setting in that case some places we're using it in high risk scenarios I have to say in general I would not treat the pelvic lymph node regions in the adjuvant setting with an undetectable PSA what about hormonal therapy and management's again you can see some using it if it was no positive disease that probably makes sense or some high risk characteristics typically not if PSA is undetectable and instead of rape the regular risk what about in the salvage setting there's a split some do some don't what about hormone therapy in the salvage setting here's an area which we'll get to later on that that is still begging for published data to support this or good data to support this but a lot of places are starting to use hormonal therapy along with radiation in the salvage setting and we'll skip over those so if indeed a man is at risk for a local failure his curative options are really to treat him with radiation earlier early or late with adjuvant or Salvage radiation therapy and so here are the studies that inform this three large randomized trials informing the use of adjuvant radiation postoperatively I would characterize us practice as early Salvage radiation despite those studies and then of course it might just be at some point too late to entertain radiation so a quick summary of the adjuvant trials three trials American European German trials all with surprisingly consistent results look at those hazard ratios almost equal in all of them suggesting very significant benefits in freedom or in progression-free survival so all very consistent in that in that regard then the American SWOG study indeed also showed a metastases free survival benefit which was it's a primary endpoint and in fact also an overall survival benefit with longer term follow-up there was us a freedom from ever needing hormone therapy and indeed the survival benefit in general was a medium two-year survival benefit with the need to treat nine patients to prevent one death that is extraordinarily strong data for the use of adjuvant radiation but what the ERC RTC trial tell us this is a trial that was recently updated about a year ago in The Lancet long-term follow-up lots of institutions a again a remarkably strong benefit and biochemical progression-free survival all the studies are consistent in that regard that is the primary endpoint oh so of this study what about clinical progression free survival that used to be significant it's an initial reporting technically now it wasn't though the trend was perhaps there and what about perhaps we would make they may argue more meaningful endpoints distant Metz prostate cancer specific mortality overall survival none of those were in fact significant in the RTC update so you have two discordant findings the American smog study showing metastases free and overall survival benefit the European study not showing those benefits all of them however showing progression-free survival benefit so why is that why are the conflicting results regarding the impact of adjuvant radiation on metastases and survival well there are a few reasons if you look at these studies closely there was an increased use of Salvage therapy in the ER TC arm for those who were initially observed and subsequently failed there was a higher rate of distant metastasis in the observation group in the SWOG trial and therefore decreased overall survival it was just a higher rate I mean pretty significantly in the observation arm in in the smog trial there was also a higher number of non cancer related deaths in the post-operative radiation group in the RTC arm so those who got adjuvant radiation in the RTC trauma trial just had a lot of unknown non cancer deaths it was it was a unexplained entirely so there are limitations to these trials the idream trials are not all truly adjuvant about a third of the patients had actually a detectable PSA at time of enrollment so these are really not truly advant studies in addition very importantly in the control arm in the observation group not all received Salvage radiation or Salvage therapy at all and most who did get Salvage therapy got it kind of too late that sort of too late part of the curve that I showed earlier in fact in the swag study and in the ROTC trip the study almost 40% got it that time of clinically or radiographically detected local failure which we would all argue is too late with a median PSA 1.7 we'll come back to that later but that PSA is too high so really these trials were adjuvant or early Salvage versus later no Salvage the question then comes out of these trials are their subgroups of patients who we shouldn't treat some say those who are t3b disease seminal vesicle invasion they're gonna do bad they're more likely to have distant disease we shouldn't treat them with adjuvant radiation a local therapy that indeed doesn't hold true in these studies in fact in the SWOG study there was a specific paper written just for the sv+ patients again showing benefit to adjuvant radiation over observation in that subgroup what the strongest predictor of benefit however of prolonged disease-free survival would surely be positive margins and that that's an important point to get across if you're considering adjuvant therapy positive margins is the right setting to do so and indeed there was actually no effect in this analysis of the euro RTC's trial in the location of those positive margins me apical wasn't worse than some other location of the positive margin indeed in the RTC trial those who did worse were those who had positive surgical margins and who were watched observed so that that might be a subgroup to consider treatment in the RTC update this is you know in general most clinical factors were trending towards benefit except aged over 70 there was another important finding from the year TC update it seemed that asthma therapy had less benefit in men who were over the age of 70 so it's it's take-home point was really consider adjuvant therapy in younger patients who have positive margins and I think that's probably the right subgroup in general morbidity was acceptable after after adjuvant therapy in the swag trial in fact if you were observed about a third required subsequent radiation and there was a doubling in the need of a subsequent hormone therapy in the adjuvant radiation arm yes rectal complications went up youth restriction rate doubled and incontinent incontinence rates were a little higher as well however interestingly in a companion quality of life study yes if you got adjuvant radiation you had acute more acute gi/gu side-effects there was however no difference in the rates of IDI however I would argue that probably surgery has evolved and this would probably be different today but they also did a global quality of life analysis and so yes global quality of life was initially worse if you got adjuvant radiation because he had more gi/gu effects but it was similar by two years and it was superior in the following three years and why would that be why because there were more cures there were there was less need for subsequent hormone therapy all of these sorts of things affecting anxiety depression and all the other side toxicities and morbidity of hormone therapy explained why long term what quality of life was better in the edge of an arm so really this comes down I'm imagine this is also a very you know it is a very relevant question in the UK to do adjuvant for all or Salvage for some and what is the optimal timing of post-operative radiation if we look at Salvage radiation series we're not informed by level one evidence yet in fact their institutional experiences this is a Hopkins study as well showing that it didn't matter if you got hormones with your radiation but it did matter that you got radiation in as opposed to not getting radiation in the salvage setting with survival benefit but in general were informed by institutional retrospective series in the salvage setting there's no more grams that have been developed that many of you are well aware of that suggests high Gleason score high PSA before initiating Salvage therapy negative surgical margins rapid PSA doubling times and seminal vesicle invasion are associated with worse outcomes or less likelihood of Salvage radiation to work doesn't mean it doesn't work it just is less likely to so let's take the best possible scenario you have a low PSA before starting Salvage radiation you had a low Gleason score to begin with your margins were positive and your PSA doubling time is long your likelihood of progression-free survival is 70% that's really quite high so you really need to think about Salvage radiation that setting what about the worst-case scenario high-grade negative margins it's working about 18% of the time so that's not zero it's not as good obviously but it's not zero so you one should still consider salvage radiation even in the negative margins hype esa hype licensed core scenario at least think about it some studies the truck study from Hopkins suggested again radiation was important as opposed to no radiation as far as outcome however it seemed to be most useful the the the values were significant when you had a rapid PSA doubling time which was sort of odd so it was in those who had rapid PSA doubling times in other series these are all retrospective one has to admit it didn't matter whether you had a rapid or a slow PSA doubling time benefit was seen in either scenario so again probably even PSA kinetics don't fully inform whether or not one should use Salvage radiation the one thing that we do know this is an important message for everybody the lower the PSA the better and when you would do initiate Salvage radiation that it whoops that's very clear in the data and that's consistent if you wait until your PSA goes above 1.5 it's much much less likely to work in fact in this nomogram there's the suggestion that there is in fact no no threshold per se that it's a continuous factor as it's suggested here pre radiotherapy PSA it seems to have a continuous effect indeed starting radiation when it's when the value is one point two or at zero point two as opposed to one point two had as much of an effect as whether or not there was lymph node metastasis present or not that just shows you the lower the PSA the better in fact some studies suggest that there's a 2.6 percent loss of relapse free survival per incremental 0.1 rise in the PSA I'm getting towards the end but the the next important question is of course as you're well aware of with radicals and other studies is the role of hormone therapy in the salvage setting indeed there is in fact a randomized trial that's been long completed but as well as one thing we've learned today you have to wait 15 years for results and even then you may still be waiting so this was started in 1996 in the RTOG bill Shipley ran this phase 3 trial lots of patients and it was radiation plus or minus two years of by kelud amide which made sense at that time doesn't make sense to us now we'd be using LHRH agonist but long term follow-up again seemingly a benefice is not published by the way it has not met its primary endpoint this is coming from a presentation seemingly a benefit in freedom from progression seemingly a benefit in metastasis free survival by the addition of hormone therapy to salvage radiation and indeed you all know this trial better than I do the radicalz trial is really looking at the timing issue of adjuvant versus early Salvage and also the use of hormone therapy and its duration in the post-operative setting I think this will be very much a practice changing trial within the ER TC in the high risk scenario after prostatectomy there's also a trial going on looking at admiration versus radiation plus six months of LHRH agonists this is important to note that imaging is getting important is getting increasingly important there are novel imaging modalities primarily MRI and PET based here's an example of lympho tropic nanoparticle lymph node mapping where it has lymph node avidity to these superparamagnetic iron oxide nanoparticles that show you disturbed nodal structure and in fact in this series of 26 post-operative PSA failures referred for Salvage radiation who are no negative and PSA was under for almost a quarter of them had subclinical incidental lymph node positivity by this imaging modality so this of course plays a role informing radiation fields or whether or not to use radiation at all depending on where this positivity is so I think you're gonna see more and more except in something we know kollene pet and other other sorts of imaging are heavier for finding a role here and this is to answer your question that I was asked earlier right by the gentleman there in the third row do you use what about pathologically node positive patients post-op node positive you just give them hormone therapy alone or should you add in radiation this is probably the best study to inform that question it's a case match analysis between a series in Italy and the Mayo Clinic that shows in fact a survival significant survival advantage to adding in radiation therapy and hormone therapy in the pathologically node-positive setting and here are the overall survival benefits at 10 years of roughly 20 percent so the answer I think although there's no level one evidence this is the best data there is these are tough patients very high-risk and there is perhaps a chance of improving outcome by referring them for consideration of radiation and hormones what about radiation field should we treat the whole pelvis or just the prostate bed no great data to inform this question either this is to - is this case matched to institutions in the u.s. one institution always treated the whole pelvis one just treated the prostate bed it appears that the whole pelvis group is doing better so again there's the reason to consider that in a salvage setting there's one trial that's addressing this issue in the RTOG rising PSA after prostatectomy three arms to this randomized trial either Salvage radiations of the post prostate bed alone Salvage radiation plus short course hormonal therapy Salvage radiation to prostate bed and no delay radiation and hormone therapy progressively more aggressive in each of those arms but you can see sort of where this field is going so in conclusion a rising PSA with a local component is relatively common for path three tumors and positive margins adjuvant radiation reduces the risk of PSA recurrence three large randomized trials are consistent with that in the need for subsequent hormonal therapy it may decrease clinical failure metastases and improve survival may underline may drtc and the smog the trials are a little discordant the benefit seems to be most concentrated among younger patients with positive margins those are the ones that consider adjuvant therapy in' though it may be seen in positive seminal vesicles rapid PSA doubling time and even node positive diseases we just saw the morbidity of this treatment appears acceptable and it is certainly lower than current systemic alternatives lifelong dangers and deprivation or other the optimal timing of radiation early Salvage versus adjuvant the field size do you conclude the nodes the role of hormonal therapy in this in the sound setting all the weight these important ongoing randomized control trials but in the meantime if you are using Salvage radiation the earlier the better the lower the PSA the better all data is consistent on that point so when surgery has probably failed to cure the patient the best prospective data still support the use of post-operative radiation it is that second chance at cure and the onus is really much on the uro oncology team to work as a team to discuss post-operative radiation with the therapy with a patient address its optimal timing when it is used and provide justification when it's not and I think that this is a nice collaborative review here on that topic with the conclusion saying given the absence of data from randomized trials demonstrate demonstrating superiority of one approach over the other meaning early adjuvant ortus or early Salvage versus adjuvant in terms of quantity and quality of life we advocate multidisciplinary input and shared and informed decision-making among patients neurologists and radiation oncologists based on the relative advantages and disadvantages of each approach and I think that fits nicely with the themes from that were raised in yesterday's session as well so thank you for your attention and thank you for having me here who's been a real pleasure [Applause]