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A Closer Look at Metastatic CRPC + Panel Discussion (all Faculty)

F. Sundram (United Kingdom)

SlotX-5 Sundram, F.

Francis Sundram talks about the individualized multidisciplinary approach required to care for patients with metastatic prostate cancer, focusing on imaging.

Transcription

Patient care in metastatic disease requires an individualised multidisciplinary approach

Metastatic prostate cancer is associated with a high level of morbidity, pain and reduced quality of life.  These disciplines need to work together to manage the disease and improve the quality of life.  

Full transcription

Full transcription

Patient care in metastatic disease requires an individualised multidisciplinary approach

Metastatic prostate cancer is associated with a high level of morbidity, pain and reduced quality of life.  These disciplines need to work together to manage the disease and improve the quality of life. 

From an imaging perspective we require a radiologist’s advice for cross-sectional imaging and interventional procedures and from a nuclear medicine specialist’s perspective for functional imaging and also radionuclide therapy.

Current Treatment Paradigm is Evolving: When to image in mCRPC?

It is clearly important to know when to image these patients.  In prostate cancer the tumour volume can vary with time and in patients with suspected metastatic disease imaging is key in restaging and subsequent treatment planning.

In the area of incremental adjuvant therapies, imaging then plays a vital role in determining if treatment is working, or if disease is progressing.

Imaging mCRPC:  Which patients to image?

Staging

Which patients should we image?  Clearly patients at high risk with a new diagnosis, including high stage T scores, Gleeson and PSA levels, suspected bone metastases, as these are the most frequent signs of disease.  Suspected lymph node metastases, particularly in the pelvis and the retroperitoneum and also in lung and liver metastases and any patient in biochemical failure following localised treatments.  All these imaging results would then determine the treatment plan for patients. 

Imaging mCRPC:  What type of imaging?

Plain films and CT

What type of imaging?  It is useful to start with plain films.  Plain films have a number of advantages and certainly in the situation where there is bone pain and the bone scan is equivocally negative, plain films can be helpful.

It can differentiate metastases from other benign pathologies, however, up to 50% of the bone content has to be altered before changes can be seen on plain films.  

Imaging mCRPC:  What type of imaging?

Plain films and CT

A CT is very useful, it can interrogate the whole body and in particular for lymph nodes, soft tissue and also the bone.  It has a reasonably high specificity for suspicious lymph nodes.  Suspicious lymph nodes can then be evaluated with fine needle aspiration cytology.

However, CT has disadvantages including a higher radiation burden compared with plain films and also it is size dependent.  Traditionally we think of bigger nodes being involved with malignancy, however, bigger nodes can also be benign and you also get conversely smaller nodes which are malignant.

Imaging mCRPC:  What type of imaging?

MRI

MRI has many advantages, certainly very high sensitivity for metastases detection.  There is no radiation involved or iodine contrast media.  Certainly for primary tumours multiparametric MRI (mpMRI) is recommended and for suspected bone and lymph node disease metastases, whole body scans or other forms of MRI imaging are advised. 

Certainly in the UK, the National Institute of Clinical Excellence, NICE, recommends mpMRI in the setting of a negative prostate biopsy and elevated PSA.  Also in staging if knowledge of T or N stage can affect the management.

Again, the disadvantage is it is probably a bit more expensive and also probably a bit more time consuming.

Imaging mCRPC: What type of imaging?

Increased sensitivity to tumour tissue with MRI

These are MRI images of a patient, so the top panel there showing the T1 weighted imaging.  Clearly we can see low signal lesions in the pelvis and also the spine, consistent with metastases.  In the bottom panel we see the MRI image of diffusion weighted imaging, so diffusion weighted imaging can detect changes in water diffusion between tissues. The normal bone marrow has a high fat content and thereby restricted diffusion.  When this normal marrow is replaced by water containing tumour cells these foci become more conspicuous as areas of increased signal.  Therefore this generates very excellent contrast between a tumour and normal tissue.

Imaging mCRPC:  What type of imaging?

Nuclear medicine bone scan – disease progression

Bone scan is widely available, is relatively cheap, you can image from top to toe and it is proven high sensitivity.  This is a patient undergoing serial imaging over a number of months and clearly we see increase in the size, the numerousy and also the intensity of these lesions, consistent with progressive osteoblastic metastases.  

Imaging mCRPC: 18F-NaF PETCT

Increased sensitivity

What about increasing the sensitivity further?  Certainly this is evident with PET bone scanning using sodium fluoride agent.  In this study it clearly shows that if you compare the PET bone scan with planar, what is called SPECT CT bone scan, there is an increase not only in sensitivity but also specificity.

Suddenly this is something that is generating a lot of interest in centres which clearly are able to do them.

Imaging mCRPC: 18F-NaF PETCT

Increased sensitivity

Just to see what it looks like on the same patient, so the patient has a planar bone scan showing a number of metastases throughout the skeleton. This is the SPECT bone scan, which in a lot of nuclear medicine departments can be done and basically you can see clearly some increased conspicuity of the lesions and also a few more numerous lesions that you can see.  This is further improved with the PET bone scan here on the right, where clearly you can see an increase in the numerousy, the conspicuity of lesions. 

All these techniques are very helpful and add incremental value to what we do.

Imaging mCRPC: FDG PETCT

What about FDG PETCT?  FDG PET is used for a variety of tumour types, so if we look at the top left-hand picture here clearly we see a nodal mass within the upper abdomen.  If you look at the PET component of that area you clearly are seeing a lack of or very little FDG activity.  If this was a lymphoma then you would expect to see a lot of activity on the PET component, but this is prostate cancer and this patient does not have any significant update corresponding to the nodal mass lesion.

Another patient with clearly multiple metastases on bone scan, on the FDG PETCT we can’t see any appreciable uptake corresponding to these bony lesions, so clearly the cancer type has a relatively low glucose metabolism and therefore there is very limited utility of FDG PETCT in prostate cancer.

Imaging mCRPC: Choline PETCT

We briefly alluded to choline PETCT.  This is a different type of PET agent and the indications broadly speaking are for a rising PSA post radical therapy.  Also in the setting of a high risk patient where there are equivocal or uncertain findings on work-up studies.

Imaging mCRPC: Choline PETCT

How does this compare with MRI?  Certainly in this study it shows that compared with MRI and choline PETCT, for lymph node metastases detection, choline PETCT is clearly more sensitive and also more specific compared with MRI.

For bone metastases the sensitivities and specificities are broadly similar. 

Imaging mCRPC: 18F-NaF PETCT

Interpreting multimodality imaging results

Multimodality approach is being increasingly used and this is a way that things are going.  This is the same patient who has been imaged using a variety of techniques.  On the left we see the sodium fluoride PET bone scan, which clearly shows multiple lesions on the skeleton.  The same patient with a planar or standard MDP bond scan showing an isolated lesion in the mid-thoracic spine. The MRI of this patient does not show any abnormality in the spine at all and the FDG PETCT is clearly negative.  The CT then shows some changes in the thoracic area of the spine.

What we can see here is that sodium fluoride PETCT is the most accurate imaging modality to use in assessing the extent of osseous or bony metastases in these patients.

Imaging mCRPC: Treatment response assessment

Interpreting PSMA PETCT results

Just to briefly touch on something called PSMA which is prostate specific membrane antigen and how it can be used as a PET agent.  PSMA is found in normal prostate cells, but obviously higher density in prostate cancer cells.  What we can do is to label PET isotopes to the PSMA.  In this patient we have used something called Gallium-68, which is a PET tracer labelled to PSMA and this image on your left, the two left ones show basically areas of increased activity above and also below the diaphragm and we can see clearly on the fused images this corresponds to nodal as well as bone metastases.  This gives us a good idea about not only bone but also soft tissue lesions. 

The isotope can then be substituted for a therapeutic isotope, so in this case lutetium, which is a beta emitter and then you can label lutetium with PSMA and then you can target and treat prostate cancer.  This is the same patient following three months of lutetium labelled PSMA and recently there is a reduced activity both in extent and in intensity above and below the diaphragm suggested of a positive response to treatment. 

Imaging mCRPC:  Treatment response assessment

Interpreting PSMA PETCT results

This came out in the news a few months ago and clearly it is a very exciting area to be involved in. Colleagues have been involved in early phase trials using therapeutic radionuclides, mainly lutetium and also actinium which is an alpha emitter, similar-ish to radium and basically they have shown very impressive drops of, falls in PSA levels following patient treatments with lutetium PSMA and also actinium labelled PSMA. 

This is all very exciting and as there is increasing evidence base over the next few years, this is a very promising technique, not only for the diagnosis but also for the treatment of prostate cancer.

Imaging mCRPC: Monitoring response to therapy

What about monitoring response to therapy?  This is one area I think we all find quite difficult.  There is no easy answer to this.  It would be interesting to hear the views of the panel as well as what they think.  Certainly the feeling is that axial skeleton MRI is the most useful tool for assessing response to therapy of bone metastases.  It has some advantages of a bone scan, whole body MRI, FDG PETCT, and we know that some of the advanced imaging modalities are not available, aren’t readily accessible in different parts of the world, so future efforts should be to try and focus on validating these new imaging techniques, ideally in trials and also making them affordable and available to us all. 

Imaging mCRPC: Monitoring response to therapy

This is a slide showing an MRI image of a patient who has been on therapy.  We can see in the lumber spine this lesion which measured about 10mm, clearly increasing in size, or doubling in size, clearly showing that treatment is not doing what it should be doing.

Discussion

Radium has been or is being increasingly used worldwide and certainly in our centre we have treated about 60 patients in the past 18 months or so.  The question becomes do you have to image these patients and if so, how frequently?

Currently there is no well-defined imaging markers for treatment response assessment and certainly bone scans were not performed in the all centre trial.

Imaging prior to three months post treatment may detect a bone flare where there could be a worsening of the bone scan appearances because of treatment related effects rather than disease progression.  In normal clinical practice what you will probably do is a bone scan and a CT scan at around eight weeks post treatment.  You probably tend to do it sometime earlier if you are suspecting the patient might be progressing after treatment, but around eight weeks would seem reasonable.  While early response assessment is obviously important, the accuracy depends on the sensitivity of what you are using to image these patients.

Other imaging done will depend on the patient symptoms, spinal cord compression, unexpected pain etcetera, and the clinical scenario.

Imaging mCRPC: Treatment response assessment following Radium-223 therapy

This is one of our patients who was treated and we can clearly see the index lesion in the posterior left rib before treatment and following six cycles of treatment we can clearly see that this lesion has improved.  In fact you would be hard pushed by just looking at this scan to say “There is something there now”.  The benefit of hindsight if you back a year there was something there, and yes, I can sort of see something there.  Clearly a positive response on the bone scan.

The sharp-eyed ones in the audience would have noticed that this patient is also having increased activity in both his collecting systems, he is on the road to being hydronephrotic and perhaps we should call one of our colleagues, perhaps the urologists or the interventional radiologist for some help.

Imaging mCRPC: Treatment response assessment following Radium-223 therapy

If you keep that picture in mind this is the CAT scan of the same patient and this is the culprit rip lesion in question before treatment and, on the right, after treatment.  Clearly there are some subtleties, but overall you say that there is some increase in the sclerosis, it won’t be in particular post-treatment. 

Here we have a situation where there is a discordance between the CT findings which show potentially some worsening and the bone scan findings which show some improvement.  This is a situation that we don’t uncommonly find in routine clinical practice.

Voting (2X)

We have kept the voting systems cold for the past few minutes, so let’s have some voting.  I am nearly finished now.

E-voting

This is the first question for the audience: if the patient is experiencing bone pain, but the bone scan is equivocal or negative, which of the following imaging technique is most appropriate?  A. we have plain films, B. axial skeleton MRI, C. Whole body MRI, D. FDG PETCT, E. Fluoride PETCT and Choline PETCT.  Please vote now.

[Vote]

We have a range of answers and those of us lucky enough to have fluoride PETCT, about a third of the audience want to go for that.  Sensibly some in the audience have talked about plain films, axial skeleton MRI; a mixture of votes here.  Okay. This is very interesting indeed.

In clinical practice it all depends on what you have, the choice of everything, modalities available, your local expertise and also the pathways that are put in place at your local tumour board for this thing. 

Maria De Santis:  May I ask a question in-between?  In the ideal world what would you recommend?  Assuming you have everything in place which imaging would you use?

Francis Sundram:  My principle really is my old anatomy professor many years ago said “Use the KISS principle”, so I would keep it simple.

Maria De Santis:  KISS principle?

Francis Sundram:  The KISS principle: keep it simple stupid!  I would keep it simple and I would probably follow the algorithm of if we have localised bone pain and the bone scan is negative, start off with a plain film to see if there are any obvious fracture or any obvious changes on that.  What we can do certainly is this bone scan, we are talking about a planar bone scan, so most departments would have access to SPECT CT bone scanning and that is a very easy technique to use; you don’t have to bring back the patient to do it at the same setting and you can add the CT component on top of that to see if there are any lesions and that improves your specificity of lesion detection and also sensitivity. 

Certainly I wouldn’t use FDG PETCT because there is no role for that and fluoride PETCT certainly has proven increased sensitivity and specificity in detecting bone metastases so I would go for that if I am concerned about disease outside the bones as well as in the bones; I would also go for choline PETCT.  I would use a multimodality approach to this patient, depending on where I think his bone metastases are.

E-voting

We will go to the next slide, which is: which of the following imaging techniques is most useful for assessment of response to bone metastases to therapy?

One we have the isotope bone scan, two CT, three whole body MRI, four axial skeleton MRI and finally PETCT.  Please vote now.

[Vote]

Very interesting.  Again about a third of our audience have indicated PETCT.  We deliberately didn’t say what type of PETCT but if you talk about a fluoride PETCT then you probably would not be wrong, or choline PETCT.  Certainly axial skeleton MRI is something that is routinely or commonly used for assessment of response.  Certainly in centres where you have whole body MRI techniques that will be something you could use as well.

In our practice we use a combination of bone scanning and also CT scanning.  It is important to know that bone scan, you can deduce or get some inference of response assessment and also to pick up any new lesions after therapy.  CT then, if you are looking at what is the next step, has this patient finished, for example, a course of radium treatment and I want to go onto the next course of treatment if I have to?  It is useful to assess if there is any progression of disease outside the bones, for example lymph nodes or liver, etcetera.

Conclusion

With that I will go to the final slide and conclude by saying there are obviously a variety of imaging modalities available.  Each one has its advantages and disadvantages. The choice of imaging depends on availability, expertise and the local pathways and imaging plays a key role in staging, treatment response assessment and disease monitoring.  There are a lot of new modalities available which I am sure are generating huge amounts of interest and it will be nice to see these coming into routine clinical practice with the evidence base available.

Certainly radiology and nuclear medicine specialists’ advice is key in determining the utilisation of these optimal imaging modalities.  Thank you.

[Applause]

Maria De Santis:  Thank you Francis.  Imaging is exciting these days and you showed us how much is on the market but, for example, with our clinical trials we have stayed with the bone scans for so many years, despite having in hand MRI and also PET scans.  If you had to design a new trial, which kind of imaging would you rather use instead of bone scan and CT scans, for example?

Francis Sundram:  There is an evidence base in terms of increased sensitivity and specificity of fluoride bone scanning.  If I had to choose which one to use for the bone then I would probably use fluoride PETCT.  We should not underestimate MRI and certainly there is experience in lots of centres, including Dr Parker’s centre in the UK, where whole body MRI can be used to very accurately represent disease status.  It would certainly be useful as well to include some of the MRI techniques in this trial.

Chris Parker: The thinking in our centre, with all respect to Francis, is very different.  In particular when it comes to measuring response in bone metastases the view at the Marsden is that bone scans and CT scans are useless.  In particular because we know from experience that if you give an active agent, the disease is responding, the patient is feeling better, the pain goes away, the PSA goes down, the bone scan can get worse, often.  It is a well-recognised flare response.  Therefore if you have another patient, the bone scan looks works is that a response, a favourable response, a flare response or is it disease progression?  You just can’t tell from the bone scan.  Our radiologists get quite emotional about this, quite heated about this and they would strongly advocate not using CT or bone scan for assessing response in the bone.  Of course it is relevant to what we were saying before about how do you monitor response to radium, because radium only works on the bone, so if you want to assess response to radium, you can’t use bone scan or CT scan.

Rather, whilst we don’t know how we should be measuring response, what we are looking at is we are currently testing whole body MRI, choline PET and fluoride PET to see which of them might be the most promising in assessing response in bone metastases.

Francis Sundram:  Just one step back, the question that becomes “Do we need to assess response following treatment?” Now the patient is clinically well and the biomarkers show us that everything is stable, the question becomes do we need to jump in and do anything at all?  Can we apply a watch and wait strategy?  That is something that we tend to do.  Clearly if there is any clinical suspicion that something is going on, despite having treatment, obviously it is nice to know whether the disease has responded to treatment or not, but certainly if one is considering other forms of treatment a baseline scan post-treatment would be useful in determining if there are any unsuspected metastases that have suddenly popped up after treatment.

Chris Parker: That is a fair point; one does need to think why is one looking for a response or progression? but there are reasons why you might want to know.  For example, if you are in a clinical trial and you want to know whether your drug is working or not and obviously you want to be able to measure response and in routine practice in many of the treatments we are using, as we know are very expensive and if you can pick up progression early and stop treatment early you can save money.  Furthermore now we have so many different active therapies, if you can stop an ineffective treatment early and switch to a new treatment earlier than you would otherwise, that is also a benefit.  There are lots of reasons why you might want to measure response and progression.

Maria De Santis: Still it has not been included or it was not included in the prostate cancer working group two and on this criteria most of our trials were based on; this might change now with a third edition of the prostate cancer, working group three, where it says that the patient should stay on treatment as long as he has a benefit.  It might make sense just to measure the benefit and to see if there is early progression, for example.  Here, most probably whole body MRI is a way to go, also to indicate early progression, which means that we should then image patients also that are asymptomatic, for example patients with stable PSA or how do you see that?  Neal, do you use whole body MRI in your practice?

Neal Shore:  We do it, but it is interesting in the US, for whatever reason, MRI is very expensive in comparison to most countries in Europe. We get a lot of push-back from our payers on excessive use of MRI.  That is just a plain, fiscal issue.

I do think whole body MRI is very good for all the reasons that were earlier said, evaluating both bone and soft tissue and less radiation exposure, so we do try to use it.  We are using a preponderance of sodium fluoride PET, but I just wanted to make one thing clear that you said, Chris, and then you said another thing – your radiologists don’t recommend getting any scanning at all?  What about the concept of a good responder to therapy, no change in symptomatology or they are asymptomatic now, but what about the concern if there is some other serologies that are going up that there could be new lesions?  Wouldn’t that be a reason to do scanning?

Chris Parker:  Sure. I was making the point that CT and bone scan are useless for assessing response in bone metastases, however, of course we do CT scans very frequently, looking at response and progression in extraosseous disease.  I wouldn’t want to imply don’t image.  Perhaps in the past our advanced prostate cancer patients hadn’t had enough imaging and so typically we will be doing CT scans every three or four months.

Maria De Santis:  My last question to the experts, perhaps all three experts, is we have the sense that the patients benefit if they can get all the treatments we have in place, so hormonal treatments, chemotherapy, both chemotherapies and radium-223; how can we best ensure that our patients will receive all the treatments in a line?  What are the criteria?  What should we look at?  What is your advice for the audience?

Neal Shore:  Chris gave that case where the patient was M0 and then sort of got M0CRPC and then got lost for a period of time.  Because of the work in nuclear medicine, radiology and all these great new scans that have much better sensitivity and specificity, the answer is the moment the patient converts from being androgen sensitive to castration resistant and they are M0 is either put them in a trial, assuming they have been scanned appropriately and regularly; no-one wants excessive costs and unnecessary radiation exposure, but picking up early detection of asymptomatic M1 disease is vital to getting in the series of therapies that we have, whether it is going to be some other version of an immunotherapy, or one of the two orals that we have now.  Then being able to get in, if you do choose to use radium, and this is very important, I think the data will ultimately bear this out – we are seeing it, the full course of treatment, the full six cycles, like in most therapies, you don’t benefit if you get only a reduced course of therapy.  Patients do a lot better if they get a minimum six to eight cycles of docetaxel as opposed to one to two.  It has to do with seeing the patient early, making sure their performance status doesn’t deteriorate so they can’t get the benefit from the therapies. 

To your point, and we said earlier, making sure they are able to be exposed to every single CRPC therapy that we have.

Maria De Santis:  Chris, would you start the heavier treatments earlier, like radium-223 or chemotherapy to ensure this?

Chris Parker: One helpful change is that following the STAMPEDE and the CHAARTED data, many patients are now getting docetaxel in the hormonal sensitive setting. That makes it easier to get in all the treatments.  If patients have not had earlier docetaxel then typically the approach we take is to use the non-toxic, or the less toxic treatments first, abiraterone, enzalutamide, radium and leave the more toxic treatments, docetaxel, cabazitaxel until later.

Maria De Santis: Francis, would you like to comment here?  More treatment to pick up the metastatic patients earlier?

Francis Sundram: If you are targeting our therapies, depending on the patient’s profile, clearly imaging has to play a huge role in selecting the right patient for the right treatment at the right time.  We need to have a close liaison with our imaging colleagues to say “What is the best modality to use?  When should we use it and how should we use it?” 

Maria De Santis: In an ideal world. This is the right point to wrap up.