A Presentation by Charles E. Myers Jr., M.D. to the Kettering Medical Center Prostate Cancer Support Group on April 25, 2002

2/17/07: Since this was given, another drug for blocking T to DHT called Avodart has come on the market.  Avodart blocks 2 pathways, while Proscar blocks one. Also, Dostinex has been found to affect the heart in Parkinson's patients using it (see Zanettini et al, NEJM, Volume 356:39-46, January 4, 2007, Number 1.)  (This update by Howard Hansen.)

For more information, Dr. Myers publishes a newsletter, "Prostate Forum."  You can subscribe to this newsletter and order earlier editions at www.prostateforum.com.

If you are interested in seeing Dr. Myers as a patient, the contact numbers are at http://www.prostateforum.com/appointments.htm

Comprehensive Management of Prostate Cancer

[Session conducted on April 25, 2002 by Dr. Charles E. Myers for the Kettering Medical Center Prostate Cancer Support Group and other interested parties. Edited slightly and section headings added by transcriber for easier readability. /jb]

Introduction
I’d like to start by taking a poll to find out how old you all are. How many people here are over 80? How many people are between 70 & 80? How many between 60 & 70? How many are between 50 & 60? Anyone under 50? I was 55 when I was diagnosed. This cancer provides different problems for each age group, so I’m going to start by talking about the very big picture of prostate cancer and its management and then get down to specifics.
 

I was diagnosed with prostate cancer myself sat the age of 55 in February of 1999. When I went in for my first screening exam, they found a nodule and a PSA of 20 which indicated locally advanced prostate cancer which was not amenable to surgery, and I had to choose a very aggressive course of radiation therapy and combined androgen blockade that went on for 18 months.
I had a long discussion with the radiation therapist, and he said he thought he could get it all, but the side effects could be major -- did I want him to go light, medium, or high? I’m a medical oncologist, and side effects didn’t particularly frighten me, and I said to go “high.” As a result, I ended up actually having to take close to two years off on medical leave because of radiation side effects.
As I came back from that time period, it completely changed my own view of prostate cancer and the problems patients deal with. I saw that there’s a real need to offer people sort of a comprehensive approach to the disease -- not just talk about whether to use radiation therapy, surgery, or hormonal therapy -- but how the disease impacts your life, what are you going to do about side effects and so on.

I went to the University of Virginia, where I was working, and proposed that we establish such a clinic, but they weren’t interested. So, beginning on February 15th of this year I retired from the University of Virginia, on February 16th I had a retirement party, and on the 18th I opened up a prostate institute in Charlottesville designed to offer patients a comprehensive approach to the disease. So this is a new adventure -- at age 58 I left the secure confines of the university to set up something independent. There are nights when I wake up with a cold sweat, more than I did for the prostate cancer...but so much for that.

The role of your overall health in decision making.

I mentioned a need for a comprehensive approach to this disease. Something that I see quite commonly is men that come to my clinic wanting advice on how to manage their prostate cancer. By the time that I get done with a physical exam it’s clear that prostate cancer’s the least of their worries: they have other disease processes they’re not afraid of that are far more dangerous. Medicare statistics show this. If you look at all men of Medicare age who have been diagnosed with prostate cancer, 39% will die of prostate cancer sometime; 31% will die of cardiovascular disease; and in fact there’s a growing literature that indicates that if you have a heart attack, you’re at a greater risk for prostate cancer, and if you’re at increased risk for prostate cancer, you’re at increased risk for a heart attack -- these things come close together. Hypertension, stroke, diabetes: these things all seem to be tied together.

So I like to tell patients that prostate cancer is like the canary in the coal mine. What it does is say that there’s something wrong with your fundamental health, not just the cancer, and you need to take a large inventory of this.

Why is this so important? Well, take someone like me who was diagnosed at age 55. The urologist says that you have a cancer that’s localized to your prostate. We can put you through surgery and give you a very good chance of being cured of the cancer. So you elect to go through major surgery with significant side effects -- some things like urinary stricture, impotence, and incontinence.

Well, does that really make sense if you’re have an underlying heart disease that’s going to kill you in five years? I think that anyone who’s going to consider radical prostatectomy or aggressive radiation therapy for his prostate ought to first ask what other diseases does he have, and are they more threatening than the prostate cancer. And if they are, what can be done about it? You have to step back after you have the diagnosis and formulate an overall health plan, rather than just think about the prostate cancer.

What kind of things are we talking about? It’s probably one of the real national scandals in the United States today is how lax the treatment of cardiovascular disease is in this country. There is now no excuse for anyone to have an elevated blood pressure. We have drugs that can normalize your blood pressure with side effects no different than a sugar capsule. Yet I still see people coming to my clinic with life-threatening hypertension. Editorials in the journals that deal with hypertension say it’s terrible that these diseases are being so undertreated.

What should your blood pressure be? You get two numbers: a high number and a low number. The low number should be below 90, and the top number ought not be above 140. If it’s above 140 you’re not being treated properly.
The same thing with cholesterol. We used to think that you should wait until you had a heart attack, heart pain, or some other symptom of heart disease before you got put on drugs that lower cholesterol. We now know that if your cholesterol is elevated, you ought to be put on drugs to lower it long before you have symptoms, and if you do that, you’re not going to get heart disease, in all likelihood.

So, all these things need to be done: cholesterol measured, blood pressure checked carefully, and tested for chemical diabetes, prior to deciding what to do about the prostate cancer.

Suppose that you have done all this, and now you have to think about what treatment to undergo. Studies show that you will tend to hear about the treatment that’s the specialty of the physician you’re seeing. Not always, but largely speaking, if you see a medical oncologist, like me, he’ll talk to you about hormonal therapy. If you see a urologist, many of them will really focus on surgery, and the radiation oncologist will focus on radiation therapy. It’s not really because they’re being self-serving, but people tend to believe in what they do. That’s why they do it. But, in fact, the proper choice of initial treatment can be quite complex.

So what I’d like to do is step back and talk to you about layers of treatment, starting with the least aggressive treatment and going all the way up through “damn the torpedoes, full speed ahead” type of approach to this disease, and what’s appropriate in various settings.

Watchful Waiting

The least aggressive approach to this disease is to do nothing. That’s called Watchful Waiting. When is that appropriate? There’s a broad consensus among people who specialize in this disease that if you have a Gleason 6 tumor or below, and your PSA is 10 or less, and you have other health problems that will kill you in ten years, then the prostate cancer is not going to affect your survival and you don’t need to do anything about it. Not everybody agrees with this consensus, but the American Urologic Association has recommended that the watchful waiting option be discussed with patients who fit this situation. But you can’t make that decision unless you’ve had a very comprehensive evaluation of your heart disease and other causes of death.

Diet and Lifestyle

I’m not a big fan of watchful waiting. We already know that by changing your lifestyle and diet you can markedly reduce the risk of hardening of the arteries, atherosclerosis, hypertension, and diabetes. A low fat diet rich in fresh fruits and vegetables can radically alter the death rate from these other diseases. It now turns out that the same diet can have a major impact on prostate cancer. So, why do nothing when if you alter your lifestyle and diet you can reduce, not only the prostate cancer’s risk of killing you, but heart disease, hypertension, and diabetes as well? You can take a single approach that alters the overall biology of the diseases you’re troubled with.

What kind of impact does this have on prostate cancer? One informative study was published in the Journal of Urology from the University of Massachusetts, this past year. They took a group of men who had radical prostatectomies and now the cancer had come back.. For these men, their PSA was doubling about every six and a half months. They were put on a low fat heart healthy diet, and now their PSA was doubling every 18 months. By just taking on the diet and lifestyle change that would be good for heart disease, they effectively tripled their survival for prostate cancer.

What kind of patients are likely to benefit? In truth, if you have a Gleason 6 carcinoma or lower, and a PSA that’s under 10, a very significant proportion of men in that group actually don’t need to do anything other than diet and lifestyle.

Jonathon Epstein at Johns Hopkins does a very useful consulting service looking at men with a Gleason of six or below, and he has a set of criteria that he uses in judging if this is a cancer that is not life-threatening. I’ve sent a number of patients to Johns Hopkins for surgery and he’ll come back with a recommendation not to do anything -- this man’s cancer is not threatening enough to subject him to surgery, and I know that they have a group of about 150 patients that they’re following with this kind of approach.
There seems to be a broad recognition among those doing research in this disease that there are a group of men with Gleason score of 6 or below who have very slowly growing cancers, and if you put them on a low fat diet you slow it down even further, and doubling times of their cancers can go out to 10 or 15 years, and nothing more needs to be done.

Right up front, if you’re newly diagnosed, one of the questions you need to ask yourself, “is that going to be enough?” I would say to you, no matter what your cancer is, and even if you’re heading for surgery or radiation, any approach that slows the prostate cancer growth down by two thirds isn’t a bad adjunct to the other things you’re doing. Especially since it’s going to improve your general health anyway. So I would think that this diet and lifestyle choice is something that everyone should adopt if they have prostate cancer, but there’s a subset of people that’s all they’ll need to do.

Drugs taken orally with few side effects

For some men this will not be enough. For them, what can we add to this program to help arrest the growth of the cancer? Or even make it shrink and disappear? Well, we now have a group of drugs that are active orally and have very few side effects, that can markedly slow the growth of prostate cancer. And, this list expands with each year.

Proscar
The list includes Proscar. Now, Proscar is not a good treatment for prostate cancer; it will not make your cancer shrink. But some randomized controlled trials show a slowing in the growth of prostate cancer with Proscar. It’s a drug that has been approved by the FDA for male pattern baldness, and for the benign swelling of the gland as men get older. It’s not very good for that purpose, but it’s pretty benign. If you wanted to commit suicide with Proscar, I don’t think you could do it. You’d probably turn blue from the pill before you got yourself in any trouble.

Proscar slows the growth of this disease by about 50% for many patients. And, if your tumor’s already doubling every two years, now it’s doubling every five years, with nothing more severe than Proscar. And when you add the diet, you can see how these improvements quickly add up, for many men.

Calcitriol

Another drug -- actually not a drug -- is the active form of vitamin D: calcitriol. It’s available now as a generic. It’s very clear that many men walk around with abnormally low levels of calcitriol, and if you simply bring their blood levels up to the high normal range, that will dramatically slow the growth of their cancer. This dose usually is about 0.5 mcg a day.

What kind of impact? I’ll give you an example. I had a lawyer from Lynchburg, Virginia, and his PSA was doubling every month. I put him on calcitriol, and now it doubles every year. It doesn’t take a rocket scientist to see that this is going to dramatically affect his long term prognosis. This man had a Gleason nine or ten, depending on which pathologist read the slide, and he had widespread bony metastases -- too numerous to count. But, were able to control his disease with one year of hormonal therapy, and for the next five years he was just on Proscar and Rocaltrol (calcitriol), which kept his disease in control until he had to go back on hormonal therapy a second time. If you’ve had any experience with prostate cancer you can realize what a change that is from the usual experience with men who have that kind of disease.

So those are two drugs that I know work; there’s very good published data on them; and they’re not terribly expensive.

Dostinex

The next drug on the list is less well known, and it’s called Dostinex. This drug is so potent you only have to take one tablet twice a week. What it does is block the production of a hormone called prolactin. This is the hormone that works with estrogen in women to cause the breast to mature during adolescence. Then later, when the woman gets pregnant, it’s the hormone that prepares the breast for lactation. As you may realize, some women don’t want to breast feed, so they need a drug to shut off prolactin production so they don’t have to breast feed. And of course, the drug has to be very safe to be used in that circumstance. This is one of the things that Dostinex does. It shuts off milk production.

It’s also probably the best single drug for Parkinson’s, but in higher doses. And, it appears to slow the progression of Alzheimer’s and other forms of dementia. About the only side effect you’ll see -- other than the loss of prolactin itself -- is that during the first week some men can get a little diarrhea, which then subsides. A very safe drug with many health benefits.

So what does prolactin do in men? The higher your prolactin, the lower your sex drive. The more prolactin, the more body fat you have. Prolactin also works with testosterone to fuel enlargement of the prostate, development of prostatitis, and also to lessen the response to hormonal therapy. None of these things are very desirable. I have found that Dostinex is very useful in reducing the growth rate of prostate cancer without causing any significant side effects. So it’s become a standard part of my armamentarium as a tool to slow the growth of the disease.

Motrin, Aleve, aspirin

Other drugs of interest that are less well established, but very promising are a group called non-steroidal anti-inflammatory drugs: Motrin, Aleve, aspirin. A number of studies show that men who are taking Motrin, Aleve, or aspirin on a daily basis have a dramatic reduction in the risk of developing prostate cancer. And now there are reports that these things can slow the progression of prostate cancer. What we don’t have are classic randomized controlled trials with a sugar pill versus Motrin or a sugar pill versus Aleve. But I’ve seen individual patients where these drugs have significantly slowed the doubling time of the prostate cancer. You may well be aware that these drugs dramatically reduce the risk of colon cancer, as well.

The major side effect of this group of drugs is that people can get ulcers, or bleeding from the stomach. If you’re one of those people, there are two things that can help make it easier to take them. One is a drug called Cytotec, which is actually a normal body metabolite that supplies what’s missing in the stomach when you’re on these drugs. Another is to take one of the drugs that reduce acid production in the stomach such as Prilosec or Nexium.

Cox-II Inhibitors
One of the most exciting things has been the development of a new class of drugs called Cox-II Inhibitors. These drugs provide pain relief such as you get with aspirin without nearly as much gastric upset. The first of these drugs is called Celebrex, which has been FDA approved for the relief of osteoarthritis. Others are Vioxx, Lodine, which has been around for a while, and a new one, Dextrim [sp.?], which is the most specific Cox-II Inhibitor of them all.
It turns out that Cox-II is not only involved in the pain of arthritis, but tumors also use it to make new blood vessels. So, in the lab, these drugs block tumor blood vessel formation and cause the arrest of tumor growth.

They are not all equal however, even though they may be equal in the relief of joint pain. Of this group, the one that is by far the most active in terms of anti-cancer activity is Celebrex...because it does something other than Cox-II. It has an activity that no one can completely understand in that it kills cancer cells. Particularly prostate cancer cells in the laboratory. Celebrex has already approved for use against colon polyps -- it will cause them to disappear in about half the people put on it. And in the laboratory it is very, very impressive in its activity against prostate cancer. And it’s like Accent for radiation therapy and chemotherapy, dramatically improving the ability of these therapies to kill this cancer.

All of these drugs that we’ve just talked about are useful tools to slow the growth of prostate cancer, and all of them combine very well with radiation therapy, and would probably be useful for patients who get radical prostatectomy, although that’s just not been studied so far. Those are the major prescription or over-the-counter drugs that we have lots of data about.

There are some other things out there that are just , very tantalizing. Many of you must know that fish oil -- the fat found in cold water fish -- has health benefits. You can go to the health food store and buy fish oil capsules. Many papers out there show that fish oil capsules will lower your cholesterol, lower your blood pressure, and can lessen the severity of diabetes. Well it turns out that men who consume lots of ocean fish or take in fish oil, have a dramatic reduction in the risk of getting prostate cancer. In the laboratory, the major fat in fish oil kills prostate cancer cells.

This information began to come to a head this past year at the University of California, San Francisco. Peter Carroll, who’s chairman of the department of urology there, had his folks look at the men for whom they’d done radical prostatectomies, which ones developed recurrent disease afterwards, and what were they eating. It turns out that if they’d had two or more servings of ocean fish a week, they had a 70% reduction in the risk that the cancer would come back after surgery. All these things point to fish oil as a dietary supplement that may well slow the growth of prostate cancer and help the other diseases that are common in men with prostate cancer.

You may know that when cancer patients are at the last stages, many times they lose weight very rapidly. As a medical oncologist, some of the patients I treat are in the end of this process. This weight loss is a very debilitating thing -- I’ve seen people lose five pounds a week, while eating as much as they could. The question is what can you do to prevent that? Well it turns out that there’s some randomized controlled trials which show that fish oil can dramatically lessen the weight loss associated with advanced prostate cancer, and other malignancies. And it reduces the bone pain as well. The irony is that this is a health element that can help in all stages of this disease. Since this paper has come out I’ve had a chance to try it in people who are in hospice care, and in fact it does help to improve their quality of life.

I might mention that calcitriol, the active form of vitamin D, also can have a dramatic impact on bone pain in end stage prostate cancer. So these are things that can help in all stages.

There’s another drug I’m sure you’ve heard about -- Thalidomide -- remember the babies without arms and legs? This drug is now available for the weight loss associated with advanced aids and cancer patients. A dose of 50 mg a day, one tablet at bedtime, is enough to significantly reduce this weight loss.
Well, it turns out that these babies were born without arms and legs because Thalidomide prevents new blood vessel formation. The folks I’d trained at NCI, after I left, looked at Thalidomide and prostate cancer and showed that, indeed, it could slow the progression of prostate cancer, at these same low doses: 50 to 100 milligrams per day. It’s also a drug that combines very well with many chemotherapy drugs.

Thalidomide comes with some baggage. It was developed as a sleeping pill, and it can be all too effective as a sleeping pill. Which is why you have to take it at bedtime. A good friend of mine who’s a prostate cancer activist, made the mistake of taking his Thalidomide at a dinner for prostate cancer activists, and he had a glass of wine. The next thing he knew, he woke up with his face in a plate of food, with a broken nose. And, you don’t want to go driving, either.
Another problem is that it can cause damage to the nerves that go to your hands and feet, so you get a numbness and tingling in the tips of your fingers and toes. This damage can be permanent, even if you stop taking Thalidomide, and can be more severe if you’re taking the drug in conjunction with some chemos. Thalidomide can be a useful drug, but you have to handle it with caution, and know that there are going to be some problems. It’s not as benign as other drugs we have talked about, but it is very, very active, in the right setting.

The final group of drugs I’m going to talk about before moving on to the next phase are drugs that are called on in diabetes. When people get adult onset diabetes, what happens is that they are making lots of insulin, but their tissues are resistant to insulin. That’s why people wind up with diabetes in their 50’s and 60’s. They’ll typically gain a lot of weight, particularly in their belly, or paunch, and that fat makes all the tissues in their body resistant to insulin. So the pancreas responds by pouring out more and more insulin trying to get ahead. Eventually the pancreas can’t produce enough insulin to overcome this resistance, the blood sugar goes up, and the person becomes diabetic.
We now know that this rarely happens as a single process. These people often have high blood pressure, high cholesterols, diabetes, and a paunch. They now call this “Syndrome X.” And since I’ve been back in practice from February on, I’ve been absolutely stunned by the number of men with prostate cancer who have Syndrome X. Statistics do show that high blood insulin levels promotes the development of prostate cancer.

There are a group of drugs that are specifically designed to overcome insulin resistance, and two of them are on the market right now. One is called Abendia, and the other’s Actos. It turns out in the laboratory, they arrest the growth of prostate cancer. Independent of their effect on insulin. My colleagues at the Dana Farber Cancer Center at Harvard have started clinical trials where they’re testing drugs in this class. It appears that, in general, these drugs arrest prostate cancer growth in about 40% of patients. And they’re looking mainly at hormone refractory patients with advanced disease. I imagine the impact would be much, much greater earlier on in the disease. In my practice so far, I have largely used these compounds only when I had patients that were already diabetic, but I have seen the arrest of prostate cancer growth in these people.

This class of drugs does come with some side effects. Ironically, although they reverse insulin resistance, one of the major side effects is weight gain. Many men will gain five or ten pounds while their on these drugs. The other is that some of them can cause liver damage. The risk is about the same as it is with Eulexin. It means that you have to have your liver function monitored every few months, just to be safe. And, you shouldn’t be consuming large amounts of alcohol if you’re on these drugs. But, again, as a tool in the armamentarium to slow the growth of this cancer, it’s a useful tool.

Hormone Therapy

Moving up to the next level of aggression, there are some men who just need the amount of cancer in their bodies reduced dramatically. There are three different ways you can do this.

One way is to get on hormonal therapy for one year: the so-called “intermittent” hormone therapy. Lupron or Zoladex, combined with Casodex (my preferred drug, I don’t like Eulexin, Casodex is simply the better drug), and I use Proscar, although that’s controversial, and many of the colleagues I respect don’t use it. Twelve months of that is often enough to reduce the number of tumor cells by 90%. Then you can come off treatment, and go on these agents that slow the growth of the disease.

This is a useful approach for patients who refuse radiation therapy or surgery, or those with medical reasons why radiation therapy or surgery can’t be done. In fact, I had a patient like that. The radiation therapist said the surgeon should do it, and the surgeon said the radiation therapist should do it. It was because he had severe hemorrhoids, and this was a risk factor for both. And these were good surgeons, they were at Memorial Sloan Kettering (radiation) and at Johns Hopkins (surgery). So there are people who benefit from intermittent hormonal therapy.

Prostatectomy

This is also a setting where radical prostatectomy is a very useful tool. It used to be that we would only consider radical prostatectomy in men whose cancers were limited to the prostate gland, and the idea was “only operate if you have a chance to cure.”

I think that the first indication that radical prostatectomy would be useful even in men whose cancer had escaped the prostate gland was work done at the Mayo Clinic by Horst Zinke, who’s Chairman of Urology there. From the 1980’s on he took men where the cancer had spread to the lymph nodes, already. He surgically removed the prostate, and in one afternoon could get rid of a billion cancer cells. That left only microscopic deposits of cancer cells in the lymph nodes, and he would then put those men on hormonal therapy.
(...short break in presentation during cassette tape turn-over...)
...a seven year follow-up [comparing surgery alone to surgery plus follow-up hormonal therapy]. After an average of seven years, only 18% of the men who had surgery alone still had an undetectable PSA, whereas more than 70% of those who had surgery followed by hormonal therapy were free of disease at the seven year mark. And even more interesting, none of these men had recurrent prostate cancer from the fifth year through the tenth year. The curve was flat at about 75% from the fifth year all the way up to the tenth year, suggesting that all the men who would relapse had relapsed, and the ones remaining may well have been cured or were candidates for cure. Even though the practice of urology has yet to catch up with these clinical trials in many places, it is well to remember that a urologist can get rid of a billion or more cancer cells in one afternoon, and that’s a very useful tool.

Radiation Therapy

The radiation therapist can do the same things. Radiation therapy is a wonderful option where you want to get rid of all the cancer cells in the prostate. It’s a very useful tool. Again, however, when the cancer’s escaped the prostate gland, it’s still worthwhile to radiate the prostate and getting hormonal therapy for the disease that’s outside the prostate. We have a whole series of randomized controlled trials to show that if you do radiation for the prostate gland and give men two years of hormonal therapy, you can rescue people who would otherwise not be rescued.

Outlook for newly diagnosed patients

So there you have a whole range of approaches that you can use for newly diagnosed patients.

In any community where PSA screening is widely done, you no longer see newly diagnosed patients with widespread involvement of their skeleton. The worst cases you are likely to see are patients whose cancer has spread to the lymph nodes. So what I’m telling you is, that if you put all these tools together, even the worst patient you’re likely to see in a community with PSA screening have an 80-90% chance of being in remission 10 years after diagnosis.

This means, basically, that we have the tools available today, if we use them, to drastically reduce the death rate from this disease. It doesn’t require new technology, it just requires taking the lessons we’ve already learned, and applying them on a community level. But it requires this comprehensive approach....of putting all the tools together.

I like to tell patients, “What you want to do is stack all the cards in your favor. You don’t want to put all your eggs in one basket, you want to put all the different tools that can control this disease together, and you want to do it in such a way that you not only keep the prostate cancer in check, but you’re going to take care of your hypertension, your atherosclerosis, and all these other things.”

I always think it’s useful to set a goal a little beyond your reach. So I like to tell patients that a reasonable goal for a newly diagnosed prostate cancer patient is to be in good health at age ninety. And, you know, you might just make it if you put all these things together. You don’t know unless you try.

Advanced disease

Now I’d like to skip over and talk about what I see as advances at the other end of the spectrum -- those patients who have widespread disease when they are diagnosed or developed later. Widespread bony disease. Here again there is an ongoing revolution occurring in what we can do for men with advanced prostate cancer.

I first started working on this disease in 1987. For the first five years that I worked on prostate cancer, the conventional wisdom was that, if you became hormone refractory, you could expect to live six to eight months.
Now, I have to tell you I can’t remember the last time I saw a patient who was hormone refractory who died less than a year after becoming hormone refractory. Mainly you’re talking a couple of years, and maybe longer than that. And I think we can do far better than even that.

I was at a meeting in West Palm Beach, and one of the young investigators from M.D. Anderson got up and presented the results of their latest sets of clinical trials. They didn’t focus on the specific drugs, but pointed out that the median survival was 36 months across all their trials for hormone refractory disease. And, they only see men with very widespread disease and the worst kind of prostate cancer in those trials. There are many men with hormone refractory disease and cancers that grow much less rapidly than this, who are going to beat those figures.

I have a patient that became hormone refractory in 1994. He had one eight-week course of chemotherapy, and then using the drugs we just outlined to arrest the growth of the disease, his cancer remained in check until 2001. He had to have another course of chemotherapy. He’s back now on suppressive therapy, and for the past two years he’s been building a major winery just south of Santa Barbara.

What I want to combat particularly is that sense of overwhelming negativism that many men get when they’ve been diagnosed with hormone refractory disease, or that their physicians communicate to them because the physicians just don’t know what we can do in the hormone refractory setting.
But, of course, if you don’t have a positive mindset, and you don’t go out and get what can be done, you’ll have a bad outcome. You know a pessimist always has his worst fears confirmed, while unexpected good things tend to happen to optimists. So, what has happened with hormone refractory prostate cancer?
The first thing is that we now have a whole group of drug combinations that can cause more than half the patients to respond, and by responding I mean they have a more than 50% drop in their PSA. You might say, “How important is it for my PSA to drop by 50%?” Well, in every cancer center that has looked at this, when every drug combination has been used, a 50% drop in your PSA translates in a double year of your survival. That’s why people are not now dying in 7 to 8 months.

“When you say a 50% response rate, that means I only have a 50-50 chance of responding.” But, this was first pointed out to me by Ken Pienta at the University of Michigan, where he looked across his series of prostate cancer patients. He said, “While only 50% respond to this combination, we have three or four combinations, and you go from one to another, and 95% of patients are going to respond to one of these combinations.” So, almost every man who has hormone refractory prostate cancer can be made to have a response to chemotherapy. We just might not get it with the first one.

Then there’s something to understand...chemotherapy will cause an initial response. Over about the first 2-3 months the PSA will drop and tumor masses will shrink, and then it will plateau. You can keep giving chemotherapy, but it’s not going to get better than that. I think that’s when we stop that chemotherapy, when you’re just keeping a lid on it.

The first person to show that this is a wise thing to do was Dan Petrylak from Columbia University. He was looking at Taxotere, which is one of the drugs we’re using. After the first 3-4 months when the response plateaued, he’d stop treatment. Then 3 or 4 months later he found he could go back in and re-treat, and using the exact same drugs the patient would respond again, and come down a plateau. Stop. Wait a couple of months, and repeat this. It’s though resistance was temporary, and disappear with 3 or 4 months off of chemotherapy.

Now, what a number of us are trying to do, and I’m not alone in this, is give the chemotherapy, drop the PSA by 50 to 90%, and then stop -- but don’t do nothing -- put the men on the drugs that slowed the growth of this cancer. In a number of patients I’m seeing, say starting with a PSA of 200, bring it down to 80 where it plateaus. Put them on drugs that keep the cancer from growing, and three months later the PSA may have gone from 80 to 100. Now you re-start chemotherapy and they go from 100 to 30. You end up going down a staircase like this, and of course the goal is to reach an undetectable PSA and complete remission. There are a number of medical oncologists who are taking this approach around the country. Already I can tell you that the quality of life is much, much better when you have a holiday off the chemotherapy. Those of you who have been on chemotherapy know how nice a holiday is.

Now there are some other things that have come out. Zometa is a drug that prevents the cancer from breaking bone down. It’s the most potent of the drugs in this series. Others include Actonel, Fosomax, Aredia. Zometa is the best of this group.

What the clinical trials show, if you have prostate cancer and you have a bony metastasis, and you’re put on Zometa, it dramatically reduces the risk that you will get new bony metastasis over the course of several years. So this is another very useful tool to prevent progression of the disease, without the side effects of chemotherapy.

Again, though, the mistake comes when the medical oncologist tries to approach this disease in piecemeal fashion and picks one of these. It’s like when you go swimming, and the water’s cold, and you stick your toe in, and inch in and how painful that is. When you’re using these approaches to the chemotherapy and hormone resistant prostate cancer, you need to do more like jumping in the cold lake right off the diving board. You need to put all the tools together that we have to approach the disease and do it in an integrated way where all phases are meant to work together.

One of the drugs we talked about at the very beginning now comes back to play a new role, Calcitriol. I think the single most exciting chemotherapy paper in the past two years was by Dr. Beer of the University of Oregon. What he showed is that if you get a single massive dose of Calcitriol 24 hours before chemotherapy, you don’t increase the side effects at all, but you dramatically increase the anti-tumor activity. He was specifically studying Taxotere, which is the most active single chemotherapy drug for prostate cancer. It took the response rate from about 40% to about 75%.

In the laboratory, the same approach dramatically improves the effectiveness of Carboplatin, another drug widely used in the treatment of prostate cancer. A number of medical oncologists are also using this. So you can see how all of these different tools that we have are suddenly more effective as we learn to use them better.

Question & Answer Session

Q: I had a rising PSA after radical prostatectomy, and in preparation for radiation treatment I started on Zoladex and Casodex for a period of 3 months. My question is: how long should I remain on hormonal therapy? The radiation oncologist suggests that a year or 18 months might prove valuable.
A: There’s some controversy about this. The question has been, and is being, addressed in a series of randomized control trials being done by the Radiation Therapy Oncology Group. This September I had dinner with Max Roach of UCSF who is heavily involved with this and will be presenting results. In their trial it looked like 2 years was optimal, but I believe they were using Zoladex alone. I happen to think that intensity matters, and Zoladex plus Casodex or Lupron plus Casodex is more effective in this setting, and that a year’s worth of Zoladex, Casodex, and Proscar is more effective that two or three years of Zoladex or Lupron alone. I actually had to “put my money where my mouth was” because I had radiation therapy and was on hormonal therapy like you, and I was planning to do it for three years. But, as this data came out, I stopped at 18 months.

Q: On DHA, how does that compare with eating fish from the ocean and taking fish oil?
A: There are no comparative studies at all, and it’s impossible for me to be sure. The fish get the DHA from the algae they eat. Plants growing in an arctic environment make a lot of DHA to keep their tissues flexible at low temperatures. It’s like a natural anti-freeze. The fish pick it up from what they eat. Salmon raised in a farm pond are fed a different diet not rich in DHA. So if you’re going to have fish, you want to make sure it grew up in the ocean, or were fed algae. You can buy DHA directly extracted from the algae in a product called Neuromins, and don’t have to pass it through a fish. The advantage of this is that it’s free from all the contaminations we worry about in ocean fish such as arsenic, lead, and organic chemicals.

Q: What do you think of using hormonal therapy to reduce the size of the prostate and then doing seed implants?
A: Well, 3 to 4 months of hormonal therapy can shrink the prostate gland down considerably and make it easier to do the seed implants. However, there is absolutely no evidence that three months of hormonal therapy before doing radiation has any impact at all on your likelihood of being cured. It’s the hormonal therapy that continues after radiation that improves survival because it targets cancer cells that may be outside the prostate. Also, killing prostate cancer cells with hormonal therapy can be done, but it is a slower process, which is why you continue it for a year or more.

Q: With hormone refractory pc, is it important to start the chemo treatments while your PSA is still low, or does it make much difference if you let it rise considerably?
A: The lower your PSA when you start chemo, the more effective. The better the chance that you will get an undetectable PSA, the longer the response, and the higher the response rate. One of the biggest mistakes I see now is the tendency of urologists to hold on to patients on hormonal therapy until the PSA gets too high and extent of the disease is too much when they get sent to the medical oncologist, and then it‘s too late for the medical oncologist to have as much impact as he otherwise would. If you’re on hormonal therapy and your PSA starts to go up, you don’t want to just sit there.
Perhaps the best analogy to bring it home, you can view hormonal therapy as a 22 caliber rifle. If you’re going after a rabbit, that’s a pretty good gun. But, if there’s an elephant charging down Main Street, you don’t want to have a 22. So, if you let the PSA get up to 100 to 1,000 and you have extensive bony mets before you switch over, you basically have an elephant charging down Main Street and you only have a 22.
Steve Strum did a nice summary of this for Ketoconozole, Nizoral, which is one of the drugs we use. It showed that if your PSA was .2 or .5, something like that, the response rate was 80%, but if you waited until your PSA reached 100, the response rate dropped dramatically. This is also true for hormonal therapy -- the lower your PSA when you start, the better the response.

Q: I’m 78 and I had a radical prostatectomy 10 years ago. I have had no therapy since, but I do walk three miles a day. I have had 35 PSA tests over the years and it has been rising slowly, doubling about every two years, and is now 24. An oncologist has told that as long as my health is good and I don’t have any aches or pains, I can forget about it and come to him if the situation changes.
A: This is a variable cancer. Some men have doubling times of 10 days, and some 10 years. He has made a very good start by looking at the biology of his own cancer by using the doubling time, which is a valuable tool. If you do nothing, you will probably develop health problems somewhere between the ages of 95 and a hundred and ten, just as you’re beginning to hit your maturity.
However, cancers can change and suddenly become more aggressive. For my patients in your setting, I do what I can to slow or arrest the growth of the cancer, and the other thing you want to do is try hard to make sure the cancer doesn’t change. The major force that fuels genetic change in prostate cancer are strong oxidants. So you should be on anti-oxidants. Vitamin E, Selenium, things like grape seed extract. In the June, 2001 issue of my newsletter Prostate Forum I cover this subject pretty thoroughly. If you want to buy yourself a lot of insurance you could go on an anti-oxidant cocktail along with Proscar and calcitriol, which also provide other health benefits.

Q: I had a radical prostatectomy on February 6. I’m now on hormone therapy. My question is, should I ask my doctor to put me on Proscar and calcitriol now, and after I go off hormone therapy, should I stay on that?
A: I happen to believe very strongly that every patient on hormonal therapy should be on treatment to prevent osteoporosis. This means Fosomax or Actonel orally, or Aredia or Zometa intravenously. And it means calcitriol.  I would never have a patient on hormonal therapy who wasn’t on calcitriol because it helps you absorb enough calcium from your diet in order to maintain bone health.

Q: He told me just to take vitamin D and calcium.
A: That’s remarkably ineffective because of why you got prostate cancer. Part of the reason why men develop prostate cancer is that they don’t activate vitamin D. In any given community, men with prostate cancer have lower levels of calcitriol in their blood than those who don’t. It’s a major risk factor. The only time I would use vitamin D is if I also had a measure of the calcitriol blood level to make sure that the patient was activating it.
This is a serious problem. Many people over the age of 50 do not activate vitamin D. And the cost isn’t just osteoporosis. It’s muscle strength, it’s mental alertness, it’s your immune function, it’s the health of your gut. One of the big arguments in aging research right now is whether everyone over a certain age ought to have calcitriol to lessen the risks of aging. There’s a nice clinical trial where they looked at people in nursing homes. When they put them on calcitriol, their grip strength increased. So, at the very least you should‘ve had your calcitriol blood level measured after you were put on vitamin D.

Q: In the June, 1999 Prostate Forum you talked about detecting early bone involvement. Two questions. First, when I read about what you did in your own personal life, I didn’t see where you did the RT-PCR nor the cytokeratin-18, and I wondered why you didn’t. The other thing is, when I read that I had the RT-PCR -- you said it could be a useful tool -- but I haven’t found anybody to help me use it after I got the results back from my micro-metastatic bone marrow test and I don’t know what to do with it now that I have the information.
A: Was it positive?
 

Q: One per million. That was after nine years of being systemic cancer. I had my surgery in 1991.
A: That’s been an evolving area. You can show that men who have microscopic cancer cells in the barrel are at some increased risk of getting overt bone metastases over time. But it’s not a perfect correlation, so it remains very controversial. The best studies I’ve seen looked not just for the presence of cancer cells, but for cancer cells that are growing.
 

Q: Is that a different test?
A: Yes. Now you’re at the ragged outer edge of what can be done. There’s a protein called MIB-1 that is only present on a cancer cell that is dividing into two. You can’t use RT-PCR, you have to use amino-histo-chemistry and look for cells that stain for PSA and MIB-1. Right now I’m working with David Bostwick to set up a method to measure whether the cells are making PSA, P53, and MIB-1. Those are the three major markers that indicate a cancer cell that might do damage by the fact that it’s in the bone marrow.
I didn’t do it for myself because it is in fact still very controversial. At the time I was doing everything to treat bone marrow metastases that were already there. The only thing I wasn’t on was chemotherapy because at that time it wasn’t where it is today. What would I do today? The technology isn’t quite there yet, but if I were able to measure the presence of cancer cells in the bone marrow that were also staining for P53, which is the major marker that indicates nasty disease, or MIB-1 positive that is growing, then I would consider chemotherapy just based on that alone.

Q: I had a six year doubling time for my PSA post radical, so I assumed I had a good P53. Is that a bad assumption?
A: In general, that’s not a bad assumption. With a six year doubling time you’re not likely to have a mutant P53.

Q: What’s the equivalency of calcitriol and over-the-counter preparations?
A: The answer is that it’s apples and oranges. The over-the-counter vitamin D has to be activated in your body, and most people over 50 don’t do a good job of it, and prostate cancer patients specifically do not.

Q: (long question -- could not understand voice)
A: I’ll take the simplest question on intermittent hormonal therapy, nine versus 12 months. The answer is no one knows. They seem to be roughly equivalent -- I’ve been using 12. That’s just arbitrary.
The 2nd question is about the dose of Celebrex. To take enough for meaningful anti-cancer activity, it’s best to take 400 milligrams twice a day. That’s the dose that makes colon polyps disappear. Of the Cox-II inhibitors, only Vioxx has been shown to increase the risk of blood clots. It has not been shown in any of the clinical trials with Celebrex.

Q: My husband is on Zoladex and I have noticed some mental deterioration.
A: Mental function in men is supported by testosterone. As men age their levels drop, and a part of the loss of intellectual function that occurs in men in their late 70’s and 80’s is simply because their testosterone isn’t what it used to be. It could affect short term memory and make men slower in solving intellectual problems. This could be one reason to consider intermittent hormonal therapy -- to restore mental function during the “off” periods. Other side effects from hormonal therapy could include higher cholesterol, higher blood pressure, and if you’re a diabetic, you’ll need to take more insulin. These are quality of life decisions in which there’s no black and white answers. Patients and physicians need to talk about it.

Q: We have heard that one milligram of Proscar is as effective as a five milligram dose for maintenance. What do you feel about that?
A: The answer is, no one knows for sure. I think it’s an individual issue. I measure the dihydrotestosterone level and adjust the Proscar dose to keep the level under five. So, I don’t have a standard dose. Some men need 30 milligrams of Proscar; others need one.

Q: When I get my PSA, can I also get that done?
A: When you get your blood draw for PSA you can also get a blood draw for dihydrotestosterone. It takes about a month to come back. When I have someone on hormonal therapy -- on or off -- I follow his testosterone, dihydrotestosterone, and PSA every three months.

Q: I’m on intermittent, and I’ve been off for a year and a half. I am taking Proscar. I take a 5 milligram tablet and cut it in half -- taking two and a half.
A: I think that’s dangerous. Proscar works by reducing dihydrotestosterone level. It’s a big mistake to use Proscar and not follow it to see how well it’s acting. It’s like having a furnace in your house and no thermostat.

Q: Along the lines of his question, I was 18 months undetectable after coming off hormone therapy when I met you in Long Beach in October of ‘99. You suggested that I go on Proscar, and I have. I’m doing a hypersensitive PSA, all zero. At some point do I stop doing Proscar?
A: No. Just looking at your head [he was bald. /jb] you’re not overdosing Proscar. [laughter]

Q: I’m 85 and have a PSA of 44. I never heard anybody say what symptoms to look for.
A: If you still have your prostate, as the PSA goes up, the cancer gets larger, you can have difficulty urinating. If the cancer’s been removed from the prostate by surgery or radiation, then you’re worried about the cancer cropping up elsewhere. One set of symptoms when the cancer goes to the bone is bone pain, or other bone changes. If it’s in the spine, the cancer can spread from the vertebrae out to press on the spinal cord, and so you can get weakness in your legs. It can spread to the lymph nodes in the back of the abdomen and block the tubes that go from your kidney to the bladder, so that can cause pain in your flank and kidney damage. Those are the kinds of things that crop up when patients aren’t getting any treatment at all. But, at a PSA of 44, most men would not have symptoms. Most men begin to have some symptoms when their PSA’s are somewhere between 250 and 1,000. I’ve got a dentist from Long Island, and when his PSA is 5,000 he can work a full day, when it gets up around 7,000 he gets tired and can’t put in a full day pulling teeth. So there’s some variation here. Different tumors do different things. Each patient is his own study.