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How best to manage patients with advanced prostate cancer presenting with high burden metastatic disease
Dr Sedelaar uses a detailed, 3-year case history to show that for every patient, treatment, diagnosis, and patient support can and should be personalized. Patients should be treated by a multidisciplinary team in a holistic approach that addresses the patient’s individual needs and wishes.
How best to manage patients with advanced prostate cancer presenting with high burden metastatic disease - Michiel Sedelaar
Francesco Montorsi: Now I would like to call on stage Professor Sedelaar from Nijmegen, who will discuss with you the role of treatment in patients with advanced disease. Michiel, the floor is yours.
Thank you very much, Francesco, for the kind invitation, also for being here able to talk to you about a case which may not be your typical case, it may be not a case you would normally see each week in your hospital; probably not even each year, but it is a case which is close to my heart and we tried to do what was possible for this man.
He presented himself three years ago with progressive micturition complaints. He went to the general practitioner and after a digital rectal examination was suspicion of a T3/4 prostate cancer.
He had a PSA of 150 and 12/12 biopsies showed a Gleason 7. This is the bad case presenting for yourself de novo.
Bone scan was negative and that could be a bit of a surprise with the high PSA, of course. The referral hospital they were already started with bicalutamide 150; I am not quite sure what the reason was but possibly they thought it would be something like a combination of prostate cancer or prostatitis.
Referral to a University Centre
The patient really needed, for himself, a second opinion and he came to our University Centre.
I saw him two weeks after the start of the bicalutamide. The micturition complaints improved slightly and the PSA was dropped to 94.4, but we did some additional investigations.
Which additional investigations would you do?
This is the first chance to use your keypads.
What would be, in your case, the chance to do some additional investigation? Either CT scan, bone scan multi-parametric MRI of the prostate, multi-parametric MRI of nodes and bones, re-evaluation of the pathology or do a second biopsy?
Imaging, not solely of the prostate, maybe not even of the prostate, but most of the people in the audience would say we need to know about the bones, you need to know about the lymph nodes and either CT scan/bone scan or MRI of the nodes.
Referral to University Centre
We did some additional imaging. Indeed, in the MRI we also saw a metastases in the sacrum, which is quite clear what we thought. We re-evaluated his histology of the biopsy and it showed at least an eight and some slight neuro-endocrine activity.
Our final diagnosis at this time is a T4N+M+Gleason 8 prostate cancer.
These are the nodes – only small, and here you see the spine with a very small lesion in the sacrum.
Keypad question: how would you change the treatment?
How would you change the treatment, because now this man is two weeks/more or less three weeks on bicalutamide? Would you continue? He had a slight symptom improvement and some slight PSA drop; would you go for a GnRH agonist/antagonist, surgical castration, combination therapy or a combination therapy with, for instance, GnRH and docetaxel or something else? Please vote.
That is how fast STAMPEDE and CHAARTED are catching up.
I think when he would present himself today I would discuss with my medical oncologists if GnRH in combination with chemotherapy would be the treatment of choice? We were three years in the past so we did have the choice of course, but the evidence wasn’t there.
Change of medication
Let’s go to the slides again. We had a long discussion about the outcome of the diagnostic test and the possible course of the disease; of course it is metastases, bone metastatic prostate cancer. It is a lethal disease. Palliative treatment, albeit it for years, but not a curative treatment.
We chose a GnRH antagonist, because it had an immediate effect on the testosterone and in months his PSA dropped to 3.9, but a couple of months later it was already rising again. His testosterone wasn’t quite low – 0.8; not low enough at last and on new imaging luckily there were no changes, no lesions at the time.
We added bicalutamide.
Some good news...
Although we know that bicalutamide doesn’t do anything on your serum testosterone, but the strange thing was that adding bicalutamide for this patient, his PSA dropped to 2.9 and his testosterone dropped to more or less somewhat more sufficient levels of 0.4 nmol/L. It was active and it was effective.
His PSA dropped 0.6; remember it came from 150 and dropped even further to 0.9.
A couple of months later he experienced side effects of the hormonal treatment – the hot flushes, the weight gain, the fatigue and he had a lot of psychological problems, both with the disease and both with his treatment; remember, he was a young man with young children who still were the same age as my children.
We did some intervention. He got a diet, physiotherapy, personal trainer and counselling and he really benefitted from the personal touch of trying to overcome those side effects of the hormonal treatment.
First signs of CRPC?
In August: bad news. His PSA started to rise and his alkaline phosphatase started to rise. Up until now his alkaline phosphatase was within boundaries of normal, but still 163 and he has new signs: he has back pain, which was treated by the general practitioner with tramadol/ibuprofen.
We did a new MRI. There is a change in the presence of this patient, there is a change in the clinical. You cannot go only solely by lab values, you need to have something more, so we did some imaging.
Prostate: decreased tumour activity, nodes – smaller nodes, but unfortunately strong progression of the bone metastases – almost his whole spine was done with bone metastases. We referred him to the radiation oncologist, Heather, for local radiation, which is sensible I think.
These early images, and remember, it is May 2013 and August 2014 and you can see all the red arrows indicating that he has multiple bone metastases up his spine.
Also in November 2013 we did some imaging and there were no additional bone mets, so he has really fast, progressive disease.
Keypad question: what is the next step?
Now what? What could be, what would be, what should be the next step in this treatment? No change, additional tests – should we see if there is something abnormal with his prostate or a metastases? Do some progression of the hormones? Start docetaxel, abiraterone and prednisone, enzalutamide, radium-223? All the options we have. Please vote.
Docetaxel is one of the favourites. Abiraterone, radium-223; is radium really indicated in symptomatic patients?
We did something else of course, otherwise I wouldn’t present his case.
New diagnostic tests
Because of the abnormal short effect of the hormonal treatment our multidisciplinary team thought we should know a little bit more about this prostate cancer.
We decided to do a re-biopsy of his prostate; see if there is neuro-endocrine activity. We saw a little bit of neuro-endocrine activity in the previous biopsies. Is there neuro-endocrine activity? Do we have ductal carcinoma? Can we see if there are genetic changes which could even influence the choice of treatment, BRCA1 and 2 mutations?
New diagnostic tests
The histology of the biopsy of the prostate showed mixed hormonal refractory adenocarcinoma, some ductal type with urothelial differentiation and acinar adenocarcinoma with still signs of hormonal sensitivity.
The neuro-endocrine activity went up from slightly less than 5% to 20% and there were no mutations.
Referral to the medical oncologist
The fact that the mutations were not there is also effective that we couldn’t give him PARP inhibition as a treatment. It is very experimental but we are in a process at our hospital that we could offer it to this patient.
New CT scans, scanning, scanning, scanning, didn’t reveal anything obvious in metastases. After consultations for the medical oncologist with some colleagues abroad, he said “Why not give the combination of docetaxel and carboplatin together with denosumab for his bones?”
Four chemotherapy cycles – positive results in the beginning, getting some reaction, positive reaction on his clinical symptoms – less pain, able to work and travel abroad, but in December 2014, more pain complaints. CT scan of the bones and nodes – there were even more progression of the bone metastases, bone scan – very positive. PSA, not even that high, whilst the alkaline phosphatase was rising again.
This is his bone scan.
Keypad question: How would you change the treatment?
How would you now change your treatment? We have already tried hormones. We have already tried chemotherapy, docetaxel and carboplatin; should we say “There is almost nothing to gain here – palliative, best supportive care.” Should we try enzalutamide? Why not abiraterone in combination with prednisone? Maybe now go for radium-223, samarium; very good for bone pain. Experimental chemotherapy – something else? Please vote.
Still a lot of people look for radium-223.
We know from studies from the ALSYMPCA trial that pain is not the first symptom you would treat with radium-223.
Secondary hormonal manipulation
December: we tried abiraterone and prednisone and I emphasise we tried; we didn’t know what to do – we tried something, abiraterone, but the bone pain kept becoming worse and worse: fentanyl patchy and oxycodone.
His PSA starts to rise to 53, his alkaline phosphatase is sky-rocketing to 565. Prednisone, given together with abiraterone was changed and dexamethasone didn’t do that much.
Question to the Panel
Panel – we have a symptomatic, very progressive patient. He is not suffering from his PSA, he is not suffering from his alkaline phosphatase, but he is suffering from his pain; anything – what could we do?
Heather Payne: I would refer him to the palliative care team to get the pain controlled, because that is the first thing that one needs to do. We would have probably given him radium at that stage, because he seems to have bone mainly progressive disease.
Michiel Sedelaar: We gave him not radium, we gave samarium. Samarium is a treatment where you should be careful to give because you already have chemotherapy, samarium is much more toxic for his bone marrow, but still it is a very good treatment for generalised bone pain. It decreases bone pain within a week. His PSA wasn’t affected, but his alkaline phosphatase was halved in two to three weeks. He was feeling much better.
Against my good advice, he went on a skiing holiday with his family.
Question to the Panel:
We now have a progressive patient, better with his bone pain, but how would we know if we are doing something right with the abiraterone? Is there still hormonal responsiveness? Do we have any way to test it? Francesco, would you have any thoughts on that?
Francesco Montorsi: It would be more important here to think about the various options that are still available. The very basic concept that should be remembered by the audience is that the original hormonal therapy should be continued; it should not be stopped. The patient, clearly, has used almost all the armamentarium that there is available. Clearly at that time you were unable to use radium, but you used samarium, which is not the same thing, but it is along the same lines and enzalutamide could be used, although the resistance can be seen in patients who have used already abiraterone or the new chemotherapy agents can be used also. Indeed, this is representing the importance of having good medical oncologists working together with us, because clearly here the decision may come only from a multidisciplinary team.
Michiel Sedelaar: We discussed this man in a multidisciplinary team. We got a very creative medical oncologist who worked in another hospital in Amsterdam, the Vrije University Hospital, where they do dihydrotestosterone PET-CET scan. It is a very new scanner, but it scans, it has labelled DHT and it will scan where DHT will go in your body. It will go to the end of the receptors. It was the kind of scan where you could say “I know where the metastases are”. If DHT goes to the metastases you must consider that there is still hormone activity; and it was. 80% of his bone metastases were still considered hormonal responses and we continue the abiraterone and dexamethasone.
DHT-PET-CT scan: imaging of the AR
For the sake of time there are the images – we are doing it in two studies in Amsterdam.
Abiraterone treatment side effects
We have some clinical improvement, so the continuation of the abiraterone gave some clinical improvement. His PSA dropped, his alkaline phosphatase was rising again, but he had to stop after a couple of months because of liver abnormalities and toxicity.
The medical oncologist changed into enzalutamide and radium. You could say after this case he got everything.
Liver enzymes were normalised, so probably the liver enzymes were due to his abiraterone or his prednisone. He had more pain again and there was a slight clinical improvement, starting with the enzalutamide and the radium-223.
Enzalutamide and radium-223
June – overall improvement, so he was still responsive to his treatment, but again, liver abnormalities. We did a CT scan – there were no metastases so it was hepatitis again and the treatment was continued.
In October a clinical progression – liver biopsy still no metastases. He got a re-challenge of abiraterone again, having a clinical response. Of course this is a strange case, but still, he responded.
November 2015: he is now done with his treatments. He didn’t respond any more. He didn’t want to have any additional chemotherapy, no cabazitaxel, which could have been even one of the next steps and he was for best supportive care.
I talked to him a couple of weeks ago; he is still alive, but he is doing not so good.
These are the PSA levels just indicating with what happens with your PSA over the course of these treatments. You see a drop, an increase, a drop again of the samarium, which is quite interesting. Here you see again responsiveness for abiraterone, stop the abiraterone and best supportive care.
ALP levels over the last 2.5 years
Alkaline phosphatase: low in the beginning, very high; again responsive to samarium and still responsive to the secondary hormonal treatment.
Lessons to be learnt
For me the lessons to be learnt for this patient – look for a personalised treatment; maybe not the treatment either so expensive or so elaborate as this patient, but try to look at this patient in a different perspective. Maybe a biopsy of his prostate could have changed the whole course of his treatment, so when you have an abnormal reaction to treatment, repeat biopsies, personalised strategies should be used for deciding the appropriate changes.
As you have seen in this case, imaging techniques should be used in a personalised fashion and patients should be treated by a multidisciplinary team, being a urologist, a medical and radiation oncologist, palliative team, pathologist, radiologist, even a physiotherapist, nuclear medicine and see the patient in a holistic way. See the person behind the patient – see the care he needs, see his troubles and the things you really have to do to make him more comfortable. Thank you very much.
Francesco Montorsi: Thank you, Michiel. This case expressed a number of concepts that for the practising urologists are important to be remembered. When you start, like in this case, treatment with degarelix you must continue this also when the patient is going to progress. The importance of multi-disciplinarity and let me add that when you have a very bad case in front of you never hesitate also to refer the patient to a major centre where he can get the care coming from a number of multiple experts.