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Determining the right patients for neoadjuvant/adjuvant therapy
Dr Payne emphasizes the complexity of treatment decisions for high-risk prostate cancer: there is no standard definition of “high risk”, and this group may include locally advanced and localized tumours with Gleason score ≥ 8 or PSA ≥ 20 ng/mL. Several treatments are recommended. Whether the best agent for long-term adjuvant androgen suppression is LHRH or GnRH is under investigation.
Determining the right patients for neoadjuvant/adjuvant therapy - Heather Payne
Francesco Montorsi: Dr Payne is going to discuss for you the talk, the title “Determining the right patients for neoadjuvant and adjuvant therapy”. We are happy to have you here with us, Heather, and the floor is yours.
Thank you; I am always very happy to be at the EAU. It is a great pleasure, and also to be talking about radiotherapy for high risk prostate cancer.
These are my disclosures.
ADT and high-risk prostate cancer
High-risk prostate cancer. We are taking it back a step and these are men that I truly believe we can make a big difference to, because these are men that we can potentially cure.
What do we mean by “high-risk”? There are several definitions. To me it is anybody who has a locally advanced tumour or localised, with a Gleason grade above 8 or a PSA above 20.
They are termed high-risk because these men give us two challenges when we treat them: they have a higher risk of disease outside the capsule, even if you can’t see it on conventional imaging and they have a high risk of microscopic metastases. These are the chaps who need combined modality treatment.
The standard has been radiotherapy with neoadjuvant concomitant and adjuvant hormones and even if I wasn’t standing here I would have to say that I am a rather enthusiastic backseat urologist, because I think for many of these men now that we are looking at complete multimodal therapy, starting with perhaps a radical prostatectomy and then going on with adjuvant treatment with radiotherapy and/or hormones, but it is an individual approach and I think there are highly selected patients who will benefit from initial de-bulking surgery.
I am going to talk mainly this evening about hormones and radiotherapy.
Rationale for neoadjuvant ADT plus RT in high-risk prostate cancer
Why do we give hormones with our radiotherapy? The first thing to think about is neoadjuvant hormone treatment, giving treatment for three to four months prior to radical radiation. Why do we do this? It shrinks the tumour and it shrinks the prostate beautifully by about 25 to 50%. This enables us to give more focussed radiotherapy with less dose going to the surrounding rectum and bladder.
Neoadjuvant treatment continuing during radiotherapy has been shown to give better outcomes than radiotherapy alone.
Case History 1
I have a case for you as well. This is an older man. He is a nice chap, he is 76, he used to be a mathematics teacher and he is extremely fit; he likes playing golf and he went to his GP because he was having difficulty getting round a whole round of golf without needing to find a convenience. He had these worsening lower urinary tract symptoms.
He was 76, he lived in the UK, he had never had a PSA blood test. He went along to his doctor; he found a large and very irregular feeling prostate gland. His first PSA was 38 and he was referred to a urology clinical for further assessment.
He had an MRI scan which showed an enlarged, 80 cc prostate gland. Sadly on imaging there was a tumour extending outside the capsule and into both seminal vesicles, but his lymph nodes were negative.
There was no evidence of bone metastases on the MRI scan or, indeed, the bone scan, so he was staged as T3B N0M0.
He underwent biopsies and all 12 cores showed Gleason 5+4. This is high risk prostate cancer and his IPSS was 14.
Keypad question: What therapy would you advise?
What would you do with this 76 year old man who has this enlarged prostate, high-risk disease, Gleason line? He is 76. Would you watch and wait? Number two would you just give him hormone treatment continuously? Would you give him intermittent hormone treatment? Would you give him radical radiotherapy with neoadjuvant and adjuvant hormones or radical prostatectomy and adjuvant treatment? Please vote now.
What do my colleagues think? He is 76? Borderline for a radical prostatectomy with local and advanced disease?
Francesco Montorsi: It depends, you said that he was very fit – if 76 is the age on the passport, but the biological age is 66, you are asking the wrong person; I would certainly take the prostate out.
Heather Payne: Admittedly he is a very fit 76 year old.
However, the decision that we made with him was that he was going to have radical radiotherapy with neoadjuvant and adjuvant hormone treatment. He did go through the MDT and was seen by my urological colleagues, but there were some concerns about operating on him so he came to me.
I treated him with bicalutamide for four weeks to prevent testosterone and potential tumour flare and then he was treated with a GnRH agonist after two weeks. He was commenced on an alpha blocker for his lower urinary tract symptoms. Of course surgery would have been the ultimate treatment for that; we could have improved his outflow obstruction.
Key trials of neoadjuvant ADT plus RT
Does neoadjuvant hormone therapy work? We talked about the theory behind that. We have a number of studies that show us that there are significant benefits by giving neoadjuvant ADT. The first study, the RTOG 86-10, with 10 years to follow-up and four months of ADT duration showed improvement in disease specific mortality, disease-free survival and biochemical failure, but made no impact on overall survival or median survival time. Is that because the treatment time was, in fact, too short for high risk patients?
TROG 96.01: Neoadjuvant ADT (3 or 6 months) plus RT vs RT alone
This study, the TROG 96.01 looked at no hormone treatment, radiotherapy alone, radiotherapy plus three months of ADT versus radiotherapy versus six months of ADT, and in this trial that was goserelin. These are interesting data.
TROG 96.01: 10 year all-cause mortality
If you look on this Kaplan-Meier, the red line at the top is radiotherapy alone, and we are looking at all-cause mortality over time. The blue line is three months of androgen deprivation therapy and the green one is six months. You can see from this there was a significant improvement with six months ADT and radiotherapy versus radiotherapy alone, given in this neoadjuvant setting. There was a difference between three and six months, with six months showing more benefit than three months. It seems like a longer time of hormone treatment is better.
Neoadjuvant ADT: Is biochemical response before RT more important than duration?
This study by Alexander changed my practice. I love this study. It was looking at is duration of hormones important or is the important factor the PSA nadir? He shows in this trial, looking at three months versus eight months of neoadjuvant hormones, that there was a significant difference in biochemical disease-free survival for those men who had a PSA nadir of less than 0.1, irrespective of the duration of their hormone treatment and that was particularly so for the men with high-risk disease.
My chap comes back at three months. His PSA is 2.2 and we would like it to be below 0.1 if possible. His testosterone is 1.9 and so his testosterone is not suppressed. He continues to have lower urinary tract symptoms and on a repeat MRI scan he also continues to have an enlarged prostate with bulky tumour.
Keypad question: What would you do next?
What would you do next? He has had his three months of hormones, would you just 1) get on with the radiotherapy, 2) would you continue for a further three months? Sometimes you see more shrinkage if you continue for six months rather than three. Would you add bicalutamide to achieve combined androgen blockade, because his testosterone is not suppressed, or would you change him to an antagonist such as degarelix? Please vote now.
What do my colleagues on the Panel think of that?
Michiel Sedelaar: I think your concern this time is not even his PSA, although we would have loved it to lower, but I think your concern is your testosterone and getting it to an antagonist could really get the testosterone down and achieve the effect you want to have, just prior to radiation.
Heather Payne: It is a very interesting vote. I will tell you what I did, was to add bicalutamide, because at that time we didn’t have degarelix available for neoadjuvant hormone treatment. Given the choice, I would be in total agreement with the majority of the people in this room because given the choice I would have changed him to degarelix. Why would I do that?
Degarelix as neoadjuvant hormone therapy
Why would I do that? Degarelix we know has a direct mechanism of action. There is a more rapid suppression of FSH, LH and testosterone and a more rapid suppression of PSA.
CS30: Degarelix vs goserelin plus antiandrogen flare protection as neoadjuvant ADT in prostate cancer
This study, the CS30, looked at patients in just this situation – for men having neoadjuvant hormone therapy prior to radiotherapy for intermediate or high risk prostate cancer. They were randomised to degarelix for three months versus goserelin with bicalutamide for the first 14 days to prevent testosterone and potential tumour flare.
The primary objective was the mean percentage reduction in total prostate volume, and this was shown to be non-inferior with degarelix as it was with goserelin and bicalutamide, both showing a reduction of 35/36% in the total prostate volume.
CS30: Significant reduction in IPSS with degarelix
There is also, and this is very interesting, that with degarelix you get this immediate action and a significant reduction in IPSS and that is important with radiotherapy because when we start treatment a lot of these men get some prostate swelling and their urinary symptoms, their LUTS worsen further. To be able to reduce their urinary symptoms in the pre-radiotherapy period, is highly important; it prevents them going into retention during treatment and makes the treatment much easier for them.
CS30: LUTS relief in symptomatic patients
As you can see here, the mean IPSS change is significantly more for degarelix than goserelin. Taking that on, what was the relief of LUTS in symptomatic patients – again greatly improved with degarelix versus goserelin and bicalutamide.
From the CS30 study it showed that degarelix is non-inferior to goserelin plus flare treatment in reducing the total prostate volume over a three month period and it seemed to provide greater relief in IPSS and LUTS, which may reduce symptoms during radiotherapy.
For that reason, given the choice, I would have then converted the man to degarelix, but I didn’t.
He continued with his agonist and bicalutamide for a further three months. His PSA did go down very nicely with combined androgen blockade, although his testosterone was still elevated, it was being blocked from having any effect. He then proceeded with radical radiotherapy and at that time we were giving 7.5 weeks 74 Gray of treatment.
He tolerated radiotherapy well with the very focussed ?R chemotherapy. He comes back to clinic and says “What happens now? Can I stop the hormones or do you need to continue?”
This is a man, if you remember Gleason 9, T3B disease, how long after radiotherapy would you advise he continues with adjuvant hormones? Three months/six months/18 months/two years or three years? Please vote now.
That is a very evidence-based answer. What do we know?
Adjuvant ADT plus RT versus RT in high-risk PCa: 10 year results
This is one of my favourite topics – adjuvant hormone treatment after radiotherapy because this has made a huge difference; this has changed practice for men with locally advanced prostate cancer and high-risk.
We have a number of studies: we have the RTOG 85-31 with more than 10 years of follow-up and a difference in overall survival over 10 years of 49 versus 39%, but this study used indefinite hormone treatment, indefinite goserelin and obviously there is a price to pay for that and a cost from being on hormone treatment for the rest of your life with non-metastatic disease.
The other US study, the RTOG 92-02, antiandrogen for four months before and during radiotherapy and then men were randomised to two years of adjuvant versus no further adjuvant treatment. Again, significant benefits in overall survival for those men with high-risk disease with Gleason 8 and above.
EORTC 22863: RT + concomitant and adjuvant ADT vs RT alone
In this study, the Bolla trial, locally advanced prostate cancer, men randomised to radiotherapy alone, or radiotherapy and goserelin for three years, starting at the beginning of their radiotherapy treatment. It is important to say with all these studies that these men would have been given probably an LH-RH agonist at that time, when they relapsed, so it wasn’t hormones versus none, it was very much the timing of the hormones in the adjuvant setting.
EORTC 22863: Improved overall survival with RT + ADT
The Bolla study is showing this hugely significant improvement in overall survival with radiotherapy and hormones at 10 years; a 40% improvement in overall survival.
EORTC 22863: Decreased prostate cancer mortality with RT + ADT
The decreased prostate cancer mortality with radiotherapy and hormones was the reason for the overall survival differences. You were less likely to die with prostate cancer if you had three years of immediate hormones rather than none at the time and then be treated for relapse.
EORTC -22961: Superior survival with long-term adjuvant ADT
In this study then Bolla looked at six months versus three years of adjuvant hormones and found that in this situation, in the 22961 study, that six months was inferior to three years. We have the 92-02 with two years adjuvant, we have the Bolla main study with three years adjuvant.
EORTC-22961: Increased overall survival and reduced prostate cancer mortality with long term adjuvant ADT
This is just showing the second study looking at short term and long term androgen suppression with a reduction in short term androgen suppression both from overall survival and deaths from prostate cancer.
Adjuvant ADT: 18 vs 36 months (PCS IV trial)
This study was reported at GU ASCO a couple of years ago and this may become the new standard of care. Instead at the moment it is between two and three years, this study looked at the difference between 18 months and 36 months of adjuvant treatment and showed that 18 months was non-inferior to 36 months, but it was thought a little longer follow-up was needed.
My man: T3B prostate cancer, Gleason line, no metastases. Six months neoadjuvant hormones, radical radiotherapy. Three years of adjuvant hormones and it is now five years since completing his radiotherapy I am pleased to say that his testosterone has returned to within normal limits, but despite that his PSA remains beautifully suppressed at 0.9, his LUTS are stable and he still enjoys a good round of golf. I think he can get round the whole course now, which is a great benefit to him.
The question at the beginning, would surgery have given him a better result? I think he has had a great result. What we don’t know yet is what multi-modality therapy would do and I think that is something that we are going to see increasingly in the future.
There are two slides that I would just like to mention, of a new study, a new EORTC study which is the 1414. This is a Phase 3, randomised study comparing radiation plus long term androgen suppression with a GnRH antagonist versus an LHRH agonist plus flare protection in this very group of men, in the high-risk localised, or locally advanced prostate cancer. This is going to be a direct comparison between agonist and antagonist.
EORTC 1414 – Trial design
At this time of the day it is a rather busy slide, but just showing that these are men with M0 disease, PSA about 10 and two risk factors of either PSA above 20, Gleason 8, T3-4, testosterone greater than 200 and age less than 80.
They are going to be treated to 78 Gray, which is now standard with radiotherapy and then will have comparison of the two different hormone regimes.
One of the other endpoints of this study is going to be looking at cardiovascular risk and looking at what happens to these men from the point of view of cardiovascular disease in the future. Therein lies another whole area of extreme interest. I know that is something that our next speaker is going to talk about. Thank you very much.
Francesco Montorsi: This was a very excellent talk that made a number of points. As I am sure that the majority of the audience is composed of urologists, think about when you go back to the hotel the role of PSA screening. We have two cases where the first, less than 50 years of age he was found with badly metastatic disease, so the whole issue of the first PSA at the age of 40 should perhaps be reconsidered. Also, the same story with this gentleman of 76 years old which presented with his first PSA done at that age. I am not saying this is right or wrong, but clearly it is something that we should think about.