Urologic Oncology

SLIDES & TRANSCRIPTS
Friday, December 5, 2003

Huggins Lecture: Radical Prostatectomy: Past, Present and Future Perspectives

Patrick C. Walsh, M.D.

Slide 1:

Thank you very much. This is a touching occasion. To be honored by your peers is something everyone looks forward to in his life, but to be honored by your peers whom you respect so much, the organization that is really doing a tremendous job in our field in educating us, I mean a program like today where all of us will leave here understanding cancer better and knowing how to treat it better is really a privilege to be honored by you.

So, I thank you very much, Ian and Jay and all of the members.

Not surprisingly when I was asked about what I would talk about I thought I might talk about radical prostatectomy, and I don't know why I picked that but it has been an exciting career working in this field and so today I thought I would talk to you about radical prostatectomy, past, present and future perspectives

Slide 2:

and this is a photograph of the Brady Institute where much of this work takes place. This is a historic building that was built in 1889.

Slide 3:

So, today's talk is going to be divided into historical perspectives principally talking about anatomic discoveries. I think a lot of young people in our field don't realize how recent some of the anatomical discoveries were made and how much we were really in the dark not too many years ago.

Next, I would like to talk about the accomplishments, where we are today and unfortunately some of the unsolved problems and finally I would like to speculate on the future.

Slide 4:

The first radical prostatectomy was performed in 1904, by Hugh Hampton Young at Johns Hopkins via the perineal technique. In 1947, Terrence Millin, an Irish surgeon developed the retropubic approach. However, by the 1970s radical prostatectomies were rarely performed even at Johns Hopkins.

Despite the fact that people believed that it was excellent cancer control, there were just too many side effects. Major bleeding was the name of the game if you did it retropubically. Virtually everyone was impotent and many patients had severe incontinence.

I came to Hopkins as you learned in 1974, and I decided that I would try to figure out why these complications occurred

Slide 5:

and I first tackled the problem with bleeding, but let me sort of fast forward and tell you what the solution turned out to be, and that is we had these complications because we did not understand or know the periprostatic anatomy. If you go back and look at any drawings of this operation prior to 1980, you saw a prostate there but you didn't see anything surrounding it. Bleeding occurred because the anatomy of the dorsal vein and Santorini's plexus was not charted. Impotence occurred because the location of the autonomic innervation to the pelvic organs and corpora cavernosa was not known and incontinence occurred because the anatomical understanding of the sphincteric complex as we understood it was incorrect.

Slide 6:

Now, this is 1974, not 1874. Why did we not know more, and the reason was because the study of periprostatic anatomy in cadavers was difficult. The solutions we used to fix the phenol dissolved away all the fatty planes and as the abdominal organs settled down there was this thick pancake of tissue that could not be dissected apart and what was the solution? The solution turned out to be using the operating room as an anatomy lab, interoperative observations and fetal dissections.

Slide 7:

So, let us talk first about bleeding. We all know now that the venous complex is over anterior surface of the prostate beneath dense fibrous tissue and because the anatomy was obscure and surgeons believed that they were doing a cancer operation excessive bleeding was inevitable.

However, as you will see on the next slide once the common trunk of the dorsal vein was identified over the urethra it became possible to develop a surgical technique that reduced bleeding and the bloodless field made it possible to perform a more precise and thorough cancer operation and one that was safer.

Slide 8:

I think we now are all aware that if you dissect away that fascia beneath it you see the dorsal vein penetrating the urogenital diaphragm and dividing into a lateral plexus on each side and a superficial branch and the key was right here to ligate the vein at its origin and that observation was made using the operating room as an anatomy laboratory.

Slide 9:

This was completed around 1977, and shortly after I developed this technique a 57-year-old man came back to see me 3 months postoperatively and he told me that he was fully potent.

At that time it was widely believed that the nerves traveled through the prostate, the cavernous nerves and that if you removed the prostate you had to cut them. So everyone had to be impotent. Well, from this one observation I realized that that was not true and the real challenge was where were these nerves, and at that time if you go to any standard anatomy textbook or anyplace else you want to look it really wasn't described, and so the steps that occurred that then led to our understanding were first some fetal dissections that I performed with Peter Donker in 1981, that gave sort of a schematic anatomy of where the nerves were, again going back to the operating room and identifying the neurovascular bundle, then as I will show you step sectioned cadaveric reconstruction and finally fresh cadaveric dissection.

Slide 10:

In 1981, I went to a surgical congress in Leiden and after spending 5 days in an anatomy lab in an operating room and in research laboratories and in the lecture hall it was Friday, February 13, and the afternoon was free before I went back to the United States and Peter Donker who I befriended a few years earlier was assigned to show me around Leiden.

Peter was retired, a retired professor of urology and he offered to show me the windmill museums or the canals and asked what I wanted to do. I was very interested in what he was doing. I said, "What are you doing now that you are retired?" a lesson for myself because Peter at that time was about my age, and he said, "Well, I am working in the anatomy laboratory," and I said, "Well, let us go see what you are doing."

So, we go and at the University of Leiden if you ever visit there they have a beautiful anatomical museum and he had a lab there and he took out an infant cadaver, a dissecting microscope and his drawings, and I said, "What are you doing?" He said, "I am dissecting out the nerves to the bladder." I said, "Why are you doing that?" He said, "Well, they have never been dissected out," for the reasons I have just given you.

I looked down and fate smiled upon us because it was a male infant and I said, "Where are the branches to the corpora cavernosa?" He said, "I have really never looked," and so we spent the afternoon and at the end of the afternoon it was very clear. Here is the pelvic plexus right here. The S2 and S3 provide the parasympathetic innervation. The thoracolumbar output goes through the hypogastric nerve, bladder, prostate, urethra in a stillborn infant, and we traced them out and here were the nerves clearly outside the capsule of the prostate outside the Denonvilliers' fascia. It was possible to preserve them.

Slide 11:

The key then came to how they could be identified. So, Peter and I agreed to work on this problem separately. He continued to do more dissections, and I came back to the States and studied the patients. I had a few other patients potent by that time. I studied them to see if they had nocturnal erections, whether the impotent patients had nocturnal erections and then I looked in the operating room and very consistently there was a group of vessels that traveled in this location, vessels that previously had been described by Flocks in 1937, as the capsular arteries and veins of the prostate.

So, we met again a year later in 1982. I told him of my thought that maybe this was the scaffolding, the neurovascular bundle if you like that could be the macroscopic landmark to identify those nerves and he said that it made sense to him and in March 1982, the first purposeful nerve-sparing operation I ever did was a radical cystectomy. I had never had a patient potent after a radical cystectomy and 10 days postoperatively the patient awoke with a normal erection.

On April 26, 1982 , I did the first purposeful nerve-sparing operation and I had the pleasure of having lunch with that man this summer. He is still continent. He is still potent and he has an undetectable PSA.

Slide 12:

So, there was proof of principle but you know we wanted more evidence. So, Herb Lepor was my resident in those days, and we took a cadaver that was completely perfused with Bouin's solution shortly after death. We excised all the pelvic organs en bloc. With the help of Kash Mostofi we made 10,000 whole mount step-sections and with the school of art as applied to medicine we did this three-dimensional reconstruction, capsule of the prostate, Denonvilliers' fascia, veins, arteries, yellow nerves, and you can see this very constant relationship between the two

Slide 13:

and next this beautiful dissection carried out by Peter Schlegel and illustrated by Leon Schlossberg which really is the template that I have in my mind every time I operate on the pelvis, the bladder, prostate, seminal vesicle. The pelvic plexus rests on the lateral surface of the rectum between 5 and 11 centimeters from the anal verge, again, getting parasympathetic innervation mainly from S2, S3, the hypogastric nerve and branches traveling of course to the bladder, to the rectum, to the seminal vesicle, the lower ureter and then of course to the prostate and eventually to the corpora cavernosa.

We now know that if one stays on the lateral surface of the seminal vesicle one can avoid the major branches here and of course the neurovascular bundle provides the major landmark that we all use.

Slide 14:

Well, why we were all men impotent? Again, this is for the younger people in the audience saying, "Well, you know because we always excised those nerves." Not really. Contrary to what you might believe the neurovascular bundles were never excised with the specimen. Instead they were bluntly torn posterolaterally where they were firmly adherent to the rectum, but and left in place. However, once the neurovascular bundles were identified it became possible to excise them where necessary thus providing a wider margin of excision.

Slide 15:

So, this is the operation we used to perform. We used to divide the urethra and I will talk more about that in a moment flush with the pelvic floor. There would be tremendous bleeding, inches of bleeding if you like, and we would then put our finger in and tear the prostate back like this. The neurovascular bundles are adherent to the rectum and so the margin at this edge was just bluntly torn and then we ligated the pedicle like this.

Slide 16:

Here is a whole mount step-section that I got from an illustration in a publication of a retropubic specimen. Here you can see part of the neurovascular bundle. Here is the BPH. Here is the cancer and you can see there was no neurovascular bundle on that side and we confirmed that even more so in the radical perineals done at Hopkins where there was never any neural tissue seen at this level.

Slide 17:

However, we are all aware now that where necessary it is possible to obtain a wider margin of excision by excising the neurovascular bundle.

Slide 18:

What about incontinence? It was believed that the external sphincter was a sandwich of muscles in the horizontal plane and Oelrich in 1980, an anatomist at the University of Michigan showed that that was not correct.

Now, it turns out, something we didn't know was that the dorsal vein complex was an important component of this tubular striated sphincter and that with refined techniques for bleeding we were able to spare injury to the striated sphincter and this improved continence.

Slide 19:

Again, this was the old concept. As Bob Myers says, it was like an apple sitting on a shelf. We believed this was the sphincter and if you divided it right here there would be no problem.

Slide 20:

However, with the misguided belief that is exactly what we did.

Slide 21:

So, this is actually what the anatomy, this is what we used to do. It was sometimes you put a, and this is from a drawing in Gleninboise(?) around 1980 showing that you just pulled up on the urethra and you divided it.

Slide 22:

Instead the striated sphincter is a tubular structure. You can see the dorsal vein of course going through it. Now, imagine what would happen if you did what we did and that is you cut right along here.

Well, the first thing that happened is this stump of the dorsal vein retracted and you couldn't stop the bleeding and secondly in doing that you excised the striated sphincter and that is why patients were incontinent.

Slide 23:

However, once the common trunk of the dorsal vein was identified this technique involved ligation and dissection beneath the complex to divide the urethra and this approach reduced blood loss and in doing so preserved the striated sphincter.

Slide 24:

So, these are the drawings from our original publication on technique for ligation and division of the dorsal vein complex and you can see the concept was to dissect beneath it and of course in doing so we were preserving the striated sphincter which was out here.

Slide 25:

So, most of these advances were in place by about 1983 and on this slide you see the proportion of men in the United States with prostate cancer treated by radical prostatectomy. The average percent of men with prostate cancer treated with radical prostatectomy in 1983, was 7 percent and within a decade by 1993, it was around 30 percent and for men in their fifties and sixties it was only 15 to 20 percent in 1983, and that rose to 50 to 70 percent a decade later.

Slide 26:

Why was surgery more popular? What happened? A number of things happened. First of all the operation was safer. There was less blood loss and there is no question that one of the major reasons that urologists did not perform radical retropubic prostatectomies was that the blood loss was absolutely frightening and dangerous to the patient.

All of a sudden we had a safer operation. Secondly, there was the perception that there was lower morbidity. Incontinence and impotence should be less, and let us face it, there were also fewer other open surgical procedures. ESWL had almost completely eliminated open stone surgery and furthermore PSA testing, more men with localized disease were available to undergo treatment.

Slide 27:

So, that is sort of the historical component of this talk. Now, I would like to focus on what I think are the accomplishments today. The first one is that the operation is definitely safer. Blood loss is less. Length of stay is lower. Thirty-day mortality has been reduced 10-fold from 2 percent to 0.2 percent.

Next, I think a major accomplishment is cancer control. Over the last 2 decades more men were subjected to potentially curative therapy. As I mentioned surgery for localized disease increased from 15 to 70 percent in men in their fifties and over the last decade deaths from prostate cancer in the United States have fallen 25 percent and I would like to connect the dots between these two with the following slides.

Slide 28:

First, a mention about cancer control, the local recurrence rate at 15 years at Hopkins is 6 percent without adjuvant treatment. In the PSA era when more men were diagnosed with curable disease, the 10-year biochemical free survival is 80 percent and I believe in the future that will reach 90 percent.

Slide 29:

The reason for that is this slide right here. This is the percent of men with organ-confined disease who underwent radical prostatectomy at Hopkins between 1982 and 1998, and you can see it was sort of going along here about the same, and I would like to point out what it is in 1992. I would like to point out it hasn't changed very much yet and I am going to make that point in a moment but you can see that once the PSA era entered today 80 percent of patients have organ-confined disease

Slide 30:

and this slide shows that in the pre-PSA era at 10 years 68 percent of patients had an undetectable PSA and in the PSA era it went up to 80 percent and I expect at least it will be 90 percent.

Slide 31:

Now, the most convincing evidence as I am sure most people in this room are aware of to document the fact that radical prostatectomy reduces cancer deaths is the Scandinavian prostate group's trial in which about 700 men, two-thirds of them with T2 disease, the other with T1 disease were randomized to undergo either a radical prostatectomy or watchful waiting.

The reason I pointed out the 1992 pathologic stage of patients is I believe that the types of patients that we were operating on, I was operating on in 1992, are very similar to these types of patients.

What they showed was at 8 years prostate cancer deaths and progression to distant metastases were reduced by 50 percent in the patients who underwent surgery.

Slide 32:

Now, here we see metastatic progression and cancer-specific survival. This is metastatic progression in the watchful waiting group which was 27 percent, metastatic progression rate in the surgery group which was 13 percent, a 14 percent difference and I think you will notice that there is a different slope to these two.

Now, recently I have become aware of some information that I hadn't thought about before. When you go back and read that paper carefully you will realize that in men who develop local progression some of them received early hormonal therapy and one knows that early hormonal therapy, where is Dr. Messing? Well, I believe that early hormonal therapy certainly delays progression but does not affect survival that much, but certainly if one group is getting more early hormonal therapy than the other these results could certainly be skewed by that.

It turns out that about half of the patients with local progression in the watchful waiting group got early hormonal therapy and half of the surgery patients, but because local progression was so much more common in the watchful waiting group 40 percent more patients in the watchful waiting group were treated with early hormonal therapy than men in the surgical group. So, if early hormonal therapy had not been given I think this would even be steeper and here we see prostate cancer, cancer-specific survival, 13 percent versus 6 percent.

Now, the next point I would like to make is that in the men who developed metastatic disease the average survival was about 2 years. So, what I would like you to do is this is 8 years right here, and if you move back to 6 years and look at this curve right here to me it looks very much like what you would expect the curve to be 2 years later in terms of deaths from prostate cancer,

Slide 33:

and so what I expect is this is the observed cancer-specific deaths and I believe within 2 years once we have 10-year data that the projected will look exactly like metastatic disease and the delta will be 14 percent.

Slide 34:

What are the implications of this? In 1993, 43,000 deaths from prostate cancer in the United States , 2003, 29,000 deaths. Why? Lots of speculation about it, but let me tell you what I think.

In 1982, when only 7 percent of men with prostate cancer underwent surgery and I think everyone will agree that radiotherapy at that time was underpowered, too underpowered to cure, essentially no one was being treated with curative intent. However, by 1992, when one-third of men underwent surgery there were 104,000 radical prostatectomies performed in the United States and if surgery reduced deaths by 14 percent at 10 years then I think that this is one of the reasons why we have had a major impact on deaths from prostate cancer.

Slide 35:

Now, critics tell us that well, hold on for a second there are some countries where early diagnosis and aggressive treatment has not been carried out and they, too, have experienced a reduction in deaths over the same interval that we have, and the answer to that is yes. There are two countries and those two countries are England and Wales and if you will look at this article by Oliver that was in Lancet you will understand why deaths from prostate cancer have gone down in England .

Here we see deaths from prostate cancer from 1970 to 1996 in the United States and the fall that we are talking about which has continued to the latest time interval, and here we see deaths from prostate cancer in Great Britain in black.

Now, in the United States and elsewhere if a patient has metastatic prostate cancer and he develops pneumonia and dies from pneumonia he is classified as a death from prostate cancer. Up until 1984, in Great Britain all of those patients were classified as dying from pneumonia.

From 1984 until 1992, they changed the definition of death and they made it what it is in the rest of the world and that is if you had prostate cancer and you died of pneumonia they called you a death from prostate cancer and in 1992, they changed the definition back to death from pneumonia.

So, the reason deaths are falling in Great Britain is they have redefined when a death from prostate cancer is and if one just makes a simple straight line between 1984 and today I don't think there has been any reduction in deaths from prostate cancer in Great Britain in a country where early diagnosis and active treatment are not aggressively pursued.

Slide 36:

Now, the second accomplishment that I think we should talk about is the impact of radical prostatectomy on research. In breast and colon cancer tissue was always available for clinical, pathological correlation and biochemical and molecular studies, and I believe this accelerated discovery in these fields. However, prior to the development of anatomic radical prostatectomy when very few men with localized disease underwent surgery only small needle biopsy specimens were available for research.

However, tissue harvested from surgical specimens I believe has galvanized research.

Slide 37:

In the past without information on pathologic stage it took many years to identify prognostic factors because of the protracted natural history of the disease.

I remember when I came to Hopkins Dr. Jewett had patients he had followed for 15 years and that was sort of the Holy Grail you know, who was alive and who had died from prostate cancer. That is all we had.

However, once we had tissue harvested at radical prostatectomies we had information on pathologic stage which provided a surrogate endpoint for long-term survival and without this information we would not understand much of what we know today about PSA for diagnosis and prognosis, for example, the Partan tables.

Slide 38:

Furthermore I think that tissue harvested at surgery has been very helpful for developing cell lines, for molecular insight into known genes and for the identification of new genes,

Slide 39:

and I would like to illustrate that with an article that was published in the New England Journal of Medicine on July 24, this year by three Hopkins scientists, Bill Nelson, Angelo DeMarzo and Bill Isaacs, and I would like to use this summary of what they did, a short summary of what they did to illustrate this, and Elizabeth Platz in the next talk is going to speak more about this.

Bill Nelson identified inactivation of the major defense mechanism against oxidative damage, methylation of GSTPI as the earliest and most universal genetic defect leading to prostate cancer, and he was able to do this because he had radical prostatectomy specimens and he could look at normal tissue in the same patient versus cancer tissue.

Angelo DeMarzo, a pathologist postulated that oxidative damage may arise from inflammation as it does in other cancers. It was known for many years that inflammation was common in the prostate but using radical prostatectomy specimens he was able to see that inflammation led to proliferative atrophy which led to a PIN, a process which is called proliferative inflammatory atrophy and finally Bill Isaacs and I for over a decade have been putting together hereditary prostate cancer families. The radical prostatectomy patients have been sort of the backbone of that study and tissue harvested from them has been very useful once we have identified genes to look for homologous deletion of those genes.

Over the last several years Bill has characterized two genes, ribonuclease L and macrophage scavenger receptor 1 in hereditary prostate cancer families that interferes with the ability of these individuals to fight off infection and I quote and this is going to be the title of Elizabeth's talk and she will tell you more about it is that these observations raise the possibility that prostate infections or inflammation may initiate prostate carcinogenesis, a whole new sort of exciting avenue into thinking about etiology and possible prevention.

Slide 40:

Now, let us face the unsolved problems. Quality of life, and wide variation in rates of continence and potency at a time when patient expectations are at an all-time high. There are more options for treatment than ever before and cancer control outcome, multiple definitions of cancer control and improvements in stage migration make cross treatment and historical comparisons meaningless.

Slide 41:

Let us talk about quality of life. We all know that there is wide variability in the rates of continence and potency at a time when patient expectations are at an all-time high. Everyone wants to play golf tomorrow, and although there are centers with great experience that report high rates of continence and potency many have not had this success.

Slide 42:

Here is an article from JAMA which was the SEER database, severe incontinence 8 percent, impotence 60 percent and they included patients as potent who were using sexual aids. So, obviously the impotence rates were much higher than that. Why is this? There was an article in the New England Journal of Medicine that came to this conclusion from Memorial Sloan-Kettering. Postoperative complications and late urinary incontinence are significantly reduced if the procedure is performed in a high-volume hospital by a surgeon who performs a high number of these procedures.

Slide 43:

The bar is rising. Twenty years ago when everyone was impotent following surgery and there were no other options the possibility for preservation of sexual function was a major improvement.

Today, however, the expectations of patients are different. They expect no side effects and the real question is can we reduce the side effects of surgery to the point where the young men who need surgery the most will accept it rather than the uncertainty of cure by other forms of treatment.

Slide 44:

The second unsolved problem I am going to address is the definition of cancer control. Many of you who deal with this problem on a day-to-day basis know that after surgery cancer control is defined as an undetectable PSA but because the PSA bounces after radiation the ASTRO criteria are used where one needs three consecutive PSA increases which are then backdated.

We recently carried out a study looking at 2700 men who were treated at Hopkins between 1985, the beginning of the PSA era and 2000 and we compared the ASTRO definition to the surgical definition and found that the ASTRO criteria inflated the probability of cure at 15 years from 68 percent to 90 percent and concluded that no one failed after 5 years.

Slide 45:

So, again, at 15 years all comers, 68 percent had an undetectable PSA. However, when we took the same data and applied them to the ASTRO criteria it was 90 percent and no one failed after 5 years and right now that is what we are hearing about radiation therapy. Everyone is cured. No one fails after 5 years.

Slide 46:

The problem is even more complicated when we look at patients who are undergoing monotherapy with brachytherapy because these individuals are truly at low risk for ever recurring and it will take years to detect cancer failure especially if the ASTRO criteria are applied. So, again, we looked at similar patients treated at Hopkins, same PSAs, clinical stage and Gleason scores as patients undergoing brachytherapy at Seattle where they have published their data on the probability of having an undetectable PSA at 10 years

Slide 47:

and in those patients who underwent brachytherapy at Seattle only 60 percent had a PSA less than .5 and at Hopkins in men undergoing radical prostatectomy during the same era with the same PSAs, Gleason scores and clinical stage 98.6 had an undetectable PSA.

Yet using the ASTRO criteria we are told about this series that 90 percent of patients were cured and no one fails after 5 years. So, I am not saying that one person is right and one person is wrong, but it is absolutely impossible, I mean I today really do not know how to compare radiation and surgery and talk to a patient and explain the likelihood of cancer control.

Slide 48:

So, what is the future? I think it must begin today or maybe yesterday, hopefully. I think that it would be wonderful if everyone could sort of decide upon guidelines. A lot of the morbidity and a variety of things relate to selection of candidates and I believe the ideal candidate for surgery is someone who is curable who is well enough to need to be cured and healthy enough to sustain the fewest side effects.

Slide 49:

Next, we have to work harder at reducing the morbidity of the procedure. One thing is improvement in education. I have been working for about 5 years to put together a DVD which is 99 percent complete. It is a 2-hour DVD with excellent illustrations. There are five different variations on how to save the nerves and I plan to give that DVD to every urologist in the world free who wants it.

Improved surgical techniques, there are lots of people in this room working on laparoscopic, robotic and perineal techniques to hasten recovery and innovative basic science approaches. Bud Burnett at our institution is working on neuro-immunophilins which in experimental models show great promise to hasten the recovery of cavernous nerve function and I believe all urologists should broadly apply quality of life surveys so that they will all know what their true outcomes are.

Next, there should be randomized and cohort comparisons of surgery versus other treatments using realistic definitions of cancer control and qualify of life. With claims that radiation curves 90 percent of men it will take many years before everyone will really know if cancer control with surgery is better and unless the side effects of surgery can be improved radical prostatectomy may well be relegated to where it was 20 years ago when everyone agreed that it was effective in curing cancer but had too many side effects to justify its widespread use.

This should not happen. This is our challenge.

Slide 50:

So, in conclusion an anatomic approach to radical prostatectomy has improved surgical exposure, has reduced blood loss, has provided excellent surgical margins, has made it possible to preserve potency, has improved urinary control, has provided excellent cancer control, in a randomized study has been shown to reduce deaths from prostate cancer and has galvanized research in the field.

I would like to thank all of you for the honor of this award and the ability to give this talk.

Thank you very much.