Current Therapies for Prostate Cancer

Introduction to Speaker and Topic

Claire Tempy is professor of Radiology at Harvard.

She's the Frank Joles Chair of Radiology research in the Department of Radiology at Brigham and Women's Hospital in Boston.

And I'm going to cover in the next 20 minutes a review of the current therapies that are used for prostate cancer.

Basically the treatments for prostate cancer, and I'm going to focus primarily in this talk on localized prostate cancer, will not be covering the advanced stages and the chemotherapy and the castrate resistant issues.

But this is primarily directed to a group of radiologists who are looking at localized disease, as we know with MRI and what is it that we can do to help our colleagues treat that patient optimally.

Basically there are four therapies of which I will cover two of these.

Primarily I will leave focal therapy and active surveillance to other talks.

I'll speak myself about focal therapy tomorrow.

And act of surveillance will be discussed later.

Overview of Localized Prostate Cancer Therapies

Looking at localized prostate cancer, what first of all is that that's of course disease that's confined to the prostate, within the capsule, quote unquote, there's surgery and there's radiation.

And then within surgery and radiation, there are many subdivisions of types of surgery and types of radiation.

Most of these are whole gland therapies, of course, and the surgery removes both the whole prostate and the local regional lymph nodes of the pelvis, pelvic sidewalls, and maybe, or maybe not most often, not the retroperitoneum.

Now, traditionally the radical prostatectomy was performed in a retropubic fashion or in the very old days, transparently.

That's still done today, but there's been some significant changes converting this to a laparoscopic procedure and a robotic assisted laparoscopic procedure using the so-called Da Vinci robot.

We'll talk more about this in a minute.

Radiation is whole gland therapy, where it's the external beam therapy or it's the placement of small micro radiation sources within the prostate known as brachytherapy.

These can be I 1 25 or palladium.

Then there's external of course, delivery of proton beam, which is a different form of radiation thought to be more focused and less toxic to adjacent organs.

And then these radiation treatments are more and more commonly, also supplemented by post-radiation androgen deprivation therapy, which is the hormonal therapy that's used to decrease the effects of testosterone on the prostate.

Background on Prostate Cancer

Now, just a little bit of a background.

We've heard a lot about prostate cancer today, and we'll continue for the next day and a half, but it is a very common disease.

We've heard how it's multifocal, it's a very complex tumor.

The biologically aggressive spectrum is not clear.

And then the conversion to castrate resistant prostate cancer, as Pete spoke about earlier, is a huge problem.

And why does that happen, and why is it that then ultimately lethal?

We're still faced today with the question to screen or not to screen to treat or not to treat.

And there's lots of data, and I'll give you a little different perspective, the same but different story that you've heard already.

It's an extremely common cancer.

Only 4% of men with prostate cancer will die of prostate cancer.

And this is race related as well.

It's higher in African Americans, more likely to be more lethal, lower in Asians.

For many people, it's an a normal aging process.

And for others, of course, it's lethal.

Screening, Overdiagnosis, and Overtreatment

And what are the numbers that really scare people into this overtreat over-diagnosis?

And overtreatment was this paper in the New England Journal of Medicine some time ago now, but it would take over 1400 men to be screened, 48 of them to be diagnosed to treat and prevent one prostate cancer death.

So you can see that really this is a huge public health issue to just to treat and to to, to treat one man, you have to go through this level of screening and this number of men diagnosed.

So the over-diagnosis and overtreatment issue continues.

Several interesting studies.

The new, the NIH itself, looking at the issue of active surveillance back in 2011, recognized this and really called upon us in the imaging community and the others in the biomarker business to try to find better ways to help distinguish these men.

One of the most sobering studies, I think that came out, which really showed the big, the little difference between no treatment and radical prostatectomy was that that came out of the va the Willett study presented in the New England Journal of Medicine in 2012.

It was a randomized control trial.

Now, there are very few randomized control trials of any in the contemporary era in any form of treatment of prostate cancer.

So this was quite a, to even get a randomized control trial done, it's criticized because it didn't ha wasn't well powered.

But 700 patients is fairly significant numbers and showed very equivalent results.

And I'll go into this in a bit more detail in a minute, between active surveillance as in no active treatment and of radical prostatectomy.

And then you've heard already from Pete today about the preventative task force issue.

And the consumer report, of course, jumped right on that when it came out with the degrade and talked about all of screening tests and basically said, please don't use PSA and gave it the usual ratings that it does for our refrigerators and our cars.

And, basically dumbed it right down.

I'm not gonna go through this in all the great detail that it really deserves in many ways, but PSA of course, unfortunately, has presented problems.

The comparison between breast cancer and prostate cancer is made many times.

With mammography, with PSA, have we really changed the world?

The answer really is unfortunately no.

Yes, we're diagnosing a little bit more localized disease and a little less advanced disease, but are we really saving lives?

It's much debated.

Decision Making for Therapy

Before you get into deciding on a course of therapy, I think there are multiple things that everybody has to understand about in a given patient.

These vary enormously.

So there's no generalizations.

First of all, of course, you confirm the diagnosis.

You're looking at things like the PSA, how rapidly has it changed?

And you're trying to try to predict is this man's cancer going to be significant or not significant?

Is it gonna kill him or is it not gonna kill em?

And there's a lot going on in there and we'll talk again later on as you've already heard about what is clinically significant prostate cancer.

But we try to get look at the velocity, the rates of change over the last couple of years, the gleasons, the estimate of tumor volume you've heard about, and of course the imaging findings that we are also interested in.

And the goal, of course, of all treatments really is not just removal, but in many places it's control.

'cause we know that this disease does not kill the majority of people that have it.

So is there a fine line between complete and total eradication versus control and balance of the quality of life and the morbidity of the disease, the stage?

We'll talk a little bit about too, because this is critical for us to understand.

The basic TNM staging focused primarily on T stage today, risk assessments, various things are happening in that field.

And as you a little bit about that already with the genetic markers that are out there, both the Polaris and the ONCA scan, and many of these genetic things that many patients are signing up for, how useful are these panels or how, how much can they be factored into the risk assessment is something we're all really learning a lot about right now.

It's still not entirely clear comorbidities should the patient have surgery or not surgery, radiation or not radiation, obviously very important.

Cardiac obesity, psychosocial anesthesia risk, et cetera.

And then life expectancy surgery is usually thought to be for the younger man, the man who has a longer life, expectancy and radiation for the man who's like a little bit less than that.

So that's sort of been the trend in the past.

And one of the most important ones is really looking at the pre-treatment baseline function, both gi, GU and sexual functions.

What are those three and how are the, how can they be impacted or changed by surgery?

And that's very important as well.

Risk Groups and NCCN Guidelines

So Dr. Dika, who I work with at the radio at the, who's a radiation oncologist at the Brigham and Dana-Farber, has for many years ago, defined what are the three risk groups for treatment, low risk, intermediate risk, and high risk.

And the data there are here, we're defining them.

As you can imagine, low risk are the Gleason three plus threes, primarily the low clinically T one C and T two A here.

He's now beginning to supplement and change that and changing it into the percent positivity at biopsy.

And then if the MRI shows three, stage three disease at high risk, and then intermediate, will be also supplemented by MRI as well.

This is the patients with the intermediate range PSAs, the Gleason Sevens, and the clinical T two B high risk patients, of course more advanced, with the Gleason eights.

These are used in the NCCN guidelines, which are the sort of the dogma of the Bible for just determining treatment.

And this is a busy slide.

I won't go through it all in detail, but really just that the T one patients are candidates for active surveillance, radical prostatectomy, brachytherapy or radiation and hormones.

So all options are on the table there.

When you get into T two, you have the same options.

And again, this is all still confined to the prostate disease.

And then stage three disease is thought not to really be a good candidate for surgery.

And I'll talk a little bit about that because that's actually changing.

There's a trend now towards operating on more and more high risk patients.

But following, the, and the NCCN guidelines, not really recommended.

MRI Staging of Prostate Cancer

So MRI staging, we've done a lot of staging.

We've been at this for many, many years, as Jeff mentioned at the beginning.

We started off in the staging business in the late eighties.

And we've got pretty good at staging prostate cancer, of course, with our techniques getting better, whether you're using E coil or three T or not, I think these things really matter somewhat when you're looking at the spatial resolution of the so-called capsule.

So T one disease is of course confined to the prostate.

I think I have little red circles that'll come up and show you these tumors in a minute.

And that's obviously the ones you've seen already with restricted diffusion in the center of the prostate that's confined to stage T one.

Stage three of course is when we start moving outta the prostate.

And you can see here in the coronal view this patient's prostate cancers invaded the capsule.

It's obliterated that nice vein line that, Deb Maum showed you earlier, which comes down along the lateral aspect here.

And you can see that cancer's grown through.

Here's another stage three tc, which is the more advanced form of three, which is into the seminal vesicles.

And you can see that nicely here at the top of the prostate or the base, significant invasion by tumor encircling all and obliterating those fluid spaces of the seminal vesicles.

And then a very advanced T four lesion here, which is invading the rectal wall.

And you can see this large tumor extended through the prostate out onto the back of the rectal wall.

So for MRI staging, and this is one without an endorectal coil, you can see here that the tumor is very nicely seen up against the capsule of the, the ci rosa of the rectum.

Goals of Treatment and Functional Outcomes

So the goals of treatment, the goals of treatment, as we've already mentioned, cure or control.

But look at, let's look at the important ones really in so far as the morbidity, the goal of treatment should be to try to preserve the urinary status, the continent status if the patient's continent before the goal should be to be continent afterwards.

Preoperative erectile function of course as well.

And there's a so-called trifecta that the surgeons and the radiation oncologists talk about, which is the cancer control, the urinary and the sexual control.

And those are the three sort of metrics of the success of a given treatment for localized prostate cancer.

So there are pre-imposed treatment assessments.

There are no particular standards that are uniformly applied because as you can imagine, reporting and determining these things is that somewhat ambiguous.

And it's a very subjective decision whether somebody really has good continence and has normal erectile function.

So there are many questionnaires and metrics out there, standardized forms of assessing this in Jim Talcott, a guy who works at the Mass General has developed one such one, which is an objective patient completed questionnaire.

And I think it's sort of an important thing.

Again, these are somewhat sensitive issues as you can imagine in a doctor's office discussing pre and postoperatively.

The, the erectile function is really not diff not easy.

And so objective patient questionnaires should be performed separately.

And this is the sort of data you want to look at in manuscripts des des describing the success of failure of various treatments.

Treatments for Advanced Disease

The current treatments for advanced are, I did said, I wouldn't speak about this, but I'm just gonna touch on it briefly.

So the androgen deprivation therapy, is used in the patients who are intermediate or more advanced.

And this can range from anywhere from six to 18 to even 36 months now as well, followed by the radiation treatment.

And so the androgen deprivation comes up front, and you will see patients on this during MRI examinations important to understand what's happening.

What it's doing is it's essentially blocking the effect of the testosterone on the prostate.

Testosterone stimulates prostate cancer growth, but not pure testosterone.

It's the testosterone that's converted to dihydrotestosterone and that's the, the metabolic pathway of that.

And so the l leuprolide or Lupron, will block all of that and then they proceed with a plus 70 plus gray over about 30 to 40 fractions of treatment over one to two months.

So it's not a trivial treatment at all.

This is a fairly lengthy procedure, and there's a lot going on to try to change that.

And I'll go into a little detail on that in a minute.

Neoadjuvant therapies are done in most of the cancer centers under trials and investigative treatments.

And these are things like enzalutamide and abiraterone, some of these showing some good success these days.

And then the castrate resistant patients really problematic as we've already touched on.

I won't belabor that this is a snapshot of that first, paper that I discussed, which was the radical prostatectomy versus active surveillance randomized control trial.

And there's a lot of data here and we don't really need to go into it in great detail.

But what it is important here is to show the age difference essentially.

All of those graphs are pretty well closely.

The two lines are the same.

And you can, even if you don't know which one is which, you can see that active surveillance and which is along the top.

They're calling it watchful waiting here.

And radical prostatectomy is the darker line.

And this is the overall total cohort of those 700 men going out for about 15 years.

And this is one of the big things about prostate cancer.

You have to follow patients for a long time after a given treatment to determine its success or failure.

And that's where the sort of the back breaks and a lot of these studies is.

They don't follow patients for long enough or you just don't get the data.

And you can see the numbers get quite small as you get out further into 15 years, but fairly equivalent overall.

And it was not statistically significant.

That difference.

Where it did become different was in the younger men and this group down here, I'm sorry, it's down at the bottom, but this is the men less than 50, 65, excuse me, 65 years of age.

You can see a separation nicely.

The radical prostatectomy patients did better, at the later time as opposed to the watchful waiting.

So in this group, it definitely did do a little bit better.

But overall, deaths from prostate cancer, very, very similar in this study.

And again, as I say, it's criticized by, as you can imagine, the constituents who had criticized the urology community as being under powered because it only had 700 patients.

The initial goal had been to enroll, I believe 1500.

And it's of course again, randomized control, trial treatment, no treatment.

That's a really tough trial to enroll in.

You're trying to tell a patient you get treated, you don't get treated, is not really the right way to do it.

Surgical Practice and Changes

So let's talk a little bit about surgical practice and what's changed and where is surgical practice today?

So the, the vast majority of prostates removed in the United States today are removed with a surgeon of course, and a robot, the Da Vinci robot.

This story in and of itself is kind of mind blowing.

This device came onto the market with minimal, if any trials of testing of any sort, and look at the number it's gone up and it's billboards like this that we used to see in the Massachusetts turnpike coming in, from the western suburbs into downtown Boston that really helped promote this.

This was a very, driven sort of technique that was driven by the, by the, the bean counters, the administrators in hospitals, the patients themselves.

There's this conception that a robot is better than a doctor.

Don't ever believe that, of course, right?

But robotics really have taken over.

There's been a lot, thank God, the globe.

Sometimes the globe is not always our friend in Boston, but at least they did suggest that you should talk to the doctor before you read the billboard to determine what type of treatment you should have.

But one of the, one of the big problems really, I think, is that the open radical prostatectomy is still an excellent procedure.

And there's no data to show that it's really that different, the outcomes from the robotic one, the difference comes in the length of stay in the hospital and the amount of blood loss.

And those are sort of essentially the two major differences that I've been able to deter, discern from the literature.

I'm not a surgeon, so there are probably other subtleties, but many of the junior trainees in urology are now being trained only in robotic radical prostatectomy.

So they're not learning how to do the open prostatectomy, which is a little bit of a tragedy because that still remains the excellent, excellent surgery.

And I heard a talk from Joel Nelson from Pittsburgh last week who presented his data with spectacular results and still very, very good meticulous surgery.

But what is the fundamental difference for a surgeon for between radical and open is the haptic feedback.

The ability to feel with your fingers is not present in robotic and laparoscopic.

And we all know that our fingers are sense of tactile sense and none of us in this room are surgeons, I don't think.

Right?

But oh, we do.

Good.

So you can tell us how important that tactile feel is so important in all forms of surgery.

So clearly, what's really also very interesting, this new paper just came out from the Hopkins group, this, this just last week.

The change in the population of patients going for radical prostatectomy.

And this has really been because of I think the trend towards active surveillance.

About 57% of the patients used to be low risk, and that number of low risk patients is declining from 10, from 2001 to two 13.

So the low risk patient numbers are going down in the surgical population and the high risk population are going up.

And that's an important trend to know about the significant variation in practice in pat in in surgical practice.

Role of Imaging in Surgery

Now, one of the things that we can do to help surgical practice, be it robotic or be it open, is to delineate the exact site of the tumor and to do what we call, at our site image segmentation, extract the information and develop 3D models that can be displayed either in your PACS workstation or separately to allow a surgeon determine the location of the tumor, the location of the external urethral sphincter and the neurovascular bundles.

All very, very important when trying to get to an optimal surgery.

So the concept here is that you display this data in front of the surgeon's visual field in some way or other.

And we do this with a laptop beside the computer for the moment, but the surgeon is sitting remote from the patient, as you know, during a da Vinci robotic prostatectomy.

And so we display this data so they can see the relationship of the tumor, be it a right-sided tumor or left-sided tumor, make decisions about whether to remove that left-sided neurovascular bundle or not make decisions about how to deep to cut down into the apex and risks in involving the external urethral sphincter.

But remembering that cancer control is the most important thing.

And so then the other concept is during the laparoscopic surgery, this is the visualization.

This is obviously the probe and the prostate is here, the tumor is invisible to the surgeon's eye.

So doing a holographic overlay of the tumor itself in green here can be potentially very helpful.

And we do this for all of Adam Al's cases, who's our chief of urology at the Brigham.

And he finds this very useful when determining whether or not where to save the neurovascular bundle on a given side of the prostate.

So as radiologists remember that delineating the volume of tumor within the prostate and describing its relationship to the adjacent neurovascular bundles very important and very helpful.

Assessment of Urethral Sphincter

One of the things that we've been looking at, and I'm so glad Masu mentioned this earlier, was the assessment of the internal and external urethral sphincter within the prostate.

When you know that there's a portion of that sphincter that's inside the prostate, the more of it that's inside the prostate, the more likely the guy is to be incontinent after surgery because of course the surgery has to remove the entire prostate.

And so we've been looking at this and I think if I go to the next slide, yep.

So we've worked with Tudor, Boraz, one of the, urology residents looking at this and showed that in three dimensional segmentation of the EUS, the external urethral sphincter, that the more of it that was outside the prostate, the more likely the patient was to be continent after surgery.

Jim, who has looked at differences between laparoscopic open laparoscopic surgery, and this is a little older paper now, but really there were significant differences in the outcomes at the beginning.

The, minimally invasive robotic surgery was significantly higher.

Rates of side effects and problems.

This has mostly gone away because a lot of this was a learning curve issue as I understand it.

And now the surgery's being performed with much greater skill because patients, surgeons have done more and more and more of them.

And like anything in medicine, the more somebody does of something, the more experienced they have, the better they get.

So be it open, be it rob robotic, as long as that surgeon has done a lot of it, then you can be sure that it'll probably be high quality.

Radiation Therapy Options

So to shift, shift gears a little bit.

Now talk about radiation.

We're looking at brachytherapy here.

Brachytherapy is the insertion of tiny little sources like the size of a grain of rice into the prostate.

They're usually placed in trans perineal using ultrasound guidance and then placed into the entire gland or into sub regions of the prostate.

And we've used MRI to delineate these areas within the prostate that may need to be treated with a higher dose.

You can do what's called dose painting and put more sources in there or more external beam in there.

And the MRI findings are very, very helpful in that situation.

And I used to work with Dr. Dko very closely on an MR guided brachytherapy program where we subs segmented the prostate like this.

And then areas where the cancer was located, we did dose escalation into that area, which then is receiving a higher radiation dose.

As you can see in red here, brachytherapy itself is also a treatment that's in decline at the moment because of costs and because of the exorbitant length of time, not, not length of time, but the really mostly because of costs.

It's not as popular now for localized prostate cancer as it was, but I think it and surgery are suffering because I think active surveillance is becoming a much more popular and more interesting treatment option.

Now that we have, imaging, as you're gonna hear later on, so we did trans peroneal placement of sources into the prostate.

You can segment the gland and you can look at the radiation doses.

It's very important to treat a little bit beyond the prostate.

And in each of these seeds, when they're placed in the gland, the radiation is limited to a three millimeter diameter around that individual seed.

So placement and, and critically, very, very important to get them in the right place.

So we at the time obviously recognize that MRI is a nice way to do this, but ultrasound is the commonest way to use, guidance modality for brachytherapy.

And the ability to register these together is obviously applicable as we've discussed in biopsy scenarios, but also very useful potentially in in ultrasound guided brachytherapy to have the MRI images fused for the radiation oncologist to guide their treatment into that area.

External Beam Radiation

And I'm gonna skip over a little bit now.

I just wanna finish up with external beam.

So external beam is the conformal 3D conformal radiation therapy.

There's also intensity modulated or IMRT, stereotactic radiation and proton beam radiation side effects pretty similar to surgery.

They usually have higher gastrointestinal or rectal proctitis as you can imagine, 'cause of the close proximity of the rectum to the prostate.

And this is one of the most challenging parts of the delivery of the beam when you're doing repeated fractionated treatments.

Over a six week or eight week period, everything will be moving and everything will be changing.

So side effects on the toxicity can be quite considerable.

They place radiation, they place small gold seeds inside the prostate.

You'll see these on your MRI scans occasionally.

These are sources placed inside to allow the medical physics and radiation oncologist to know where the prostate is, be they using plain film or cone beam CT scan during the treatment.

So these three little guys here are the gold seeds that are so-called that are placed and you can see them on the plain x-ray there.

So these are placed by a urologist typically and by, using ultrasound, and doing just like they would for a biopsy, but instead of taking tissue, they're putting in the gold sources.

And so we do a little bit of, external beam brachytherapy in our facility using the MRI scanner, also to delineate sub sub regions and we've used ultrasound as well and MRI together to really try to explore better the fusion and the, the ability to delineate the tumor.

One concept, and I don't wanna go into detail of everything on this slide, but just to show you how much motion can occur within a given prostate over just 40 minutes.

So just watch that video and you can see everything's moving there over 40 minutes.

So one of the things, I wanted just con the concept to get across is those gold seeds are very important.

The gold seeds help them track that prostate, but not really very well because they're really only three sources within the prostate.

Effects of Androgen Deprivation and Response Assessment

One of the other things that you can use MRI for is to assess the volume changes in tumors.

And this is a very old side where we were looking at androgen deprivation.

I just want the concept of what androgen deprivation does to the prostate.

To be clear, it will shrink the entire prostate itself and shrink the tumor as well.

So you get this generalized volume loss over, two months of androgen deprivation therapy.

One of the other advantages of MRI is you can use things like CPMG technique or diffusion or any of the parameters, some of them better than others to look at the sensitivity for the change, the interval change in neoadjuvant chemotherapy in patients, before radiation.

MRI for response assessment.

We'll touch on this much more in greater detail in in, in later talks.

But here to see, to show you is just what happens after ablation.

You can see necrosis within the prostate.

And then one of the important ones is to look for recurrence inside a radiated prostate.

And that can really be quite challenging because the T two weighted images after radiation will not show tumor very well because the entire prostate will be low signal.

And so you can see the diffuse low signal here, but the gadolinium is very helpful in this scenario.

And this is where I think we will continue to require DCE imaging is in a lot of these post-treatment cases.

So that I will conclude, therapies, prostate cancer.