Dr. Catalona's Talk to Man to ManJuly 26, 2001
(Introduction of Dr. Catalona by Dr. Paul Cohen)
Thank you very much. I am very pleased and privileged to be here, not only because of the degree of respect I have for Dr. Catalona, but because I feel like I'm part of your group in that I have many patients who have been coming to Man-to-Man for quite a while and I hear only excellent things about your group. For me, it has always been inspirational to meet a superb clinician, or a superb educator, or a superb scientist. Clearly what makes Dr. Catalona so extraordinary is that he has excelled in all three arenas, something that very few people in American Medicine have done. He trained at Yale in medical school and he went on to do his residency training at NIH and John Hopkins and has been at Washington University and has been an outstanding surgeon and Chairman of Urology there for many years. He has been a pioneer in the field of nerve-sparing prostate cancer surgery, as many of you or all of you already know. He has transmitted this to many other physicians through many modalities, not only in the OR but also through his lecturing and videotapes and all the medical literature that he has produced. Two major advances in the field of detection and monitoring of prostate cancer have really been the result of his original research. He took the PSA from a test that was from the laboratory and it became an early detection for prostate cancer as a result of his paper in The New England Journal in 1991, and when the free PSA became invented, he again took this laboratory test and was able to use that as a discriminatory tool in distinguishing benign and malignant disease of the prostate gland. Both of those contributions alone or either one of them would have been the kind of contribution that any person in Medicine would have dreamed of being able to do in their lifetime and he did that, plus all the incredible surgery that has gone on in nerve-sparing, so his contributions have been outstanding, as well as all the contribution to the people who are fortunate enough to train under his tutelage when he was attending their surgical training programs.
My first contact with Dr. Catalona was actually five years ago when one of my patients went to Washington University and came back raving about the outstanding care that they received. Obviously, the surgical outcome, all of you know, is incontestably the finest in the states, but what I was so impressed with, because since then I've had probably about a dozen of my patients go to Washington University, is that this man, who is so outstanding and remains very, very connected to his patients, has been incredibly compassionate to them, caring, spends the time to sit down and be with them despite a schedule that must be like a hurricane coming in, and he seems to get it all done with incredible grace, and the patients feel like they have met him and gotten to know him, and it's really an amazing thing that he can do all that. So, we're all grateful to Dr. Catalona for the contributions that he has made to the field of Medicine and specifically, the field of prostate disease, and it is truly my privilege to introduce him.
Early Diagnosis and Treatment of Localized Prostate Cancer
Thank you very much, Dr. Cohen. I can return your compliments because I've heard so many wonderful things about you from your patients, and it really is a privilege and an honor for me to get to meet you after all this time that we have communicated with one another about patients. It's a special pleasure for me to be here because I do have many patients and friends in the Syracuse area. I would especially like to thank my good friend and patient, Jules Reichel, for inviting me to come here to speak. We all know how much Jules does for prostate cancer patients.
The key to good results in treating localized prostate cancer is to make the diagnosis as early as possible. It is now possible to detect at least 80% of prostate cancers while they are still totally contained within the prostate, and to cure 90% of prostate cancers if early diagnosis and effective treatments are used appropriately.
The other point that I would like to emphasize today is that there is no one treatment that is best for every patient; different patients have different types of disease and different host factors that affect treatment choice. Therefore, the best treatment for Patient A may not necessarily be the best treatment for Patient B.
As Dr. Cohen mentioned, we developed the PSA test as an early detection test for prostate cancer. I started our PSA screening study in 1989 and that study has now enrolled about 35,000 men. When we initially published the results of our study, we set the normal level for PSA at 4 and that has been pretty much accepted around the world as the standard. Thus, it has been generally believed that if a man's PSA is less than 4, it's normal, and if it's above 4, then that's worrisome that he may have prostate cancer. However, within a few years of starting the study, it became apparent to me that a lot of the men whose PSA was higher than 2.5 were on the way up, and 50% of these men had a PSA that was higher than 4 within a few years. So, in 1995, we lowered the PSA cutoff level to 2.5 in our study, and we found that about 22% of men who had a PSA between 2.5 and 4 had prostate cancer detected on biopsy.
Although, I am in the minority using this lower cut off in the US, things are changing. In large screening studies in Europe and in Quebec, they use a cutoff of 3. A study performed at the MD Anderson Hospital also found that about 24% of patients with a PSA of 2.5 to 4 had prostate cancer. The important difference is that when you use the 4 cutoff, you detect about 70% of the prostate cancers while they are still organ-confined; whereas, if you use the 2.5 cutoff, you can detect 80 or 8% of cancers while they are localized to the prostate.
It also has become apparent that biopsies can miss a lot of prostate cancers. When you take only six tissue cores from the prostate, you miss at least 25% of the detectable prostate cancers. I use the analogy that it's just like taking a piece of hay from a haystack; that is, you obtain only a very small sample of the prostate. The solution to this problem is for the doctor to take more biopsy cores initially. Recently, we have learned how to anesthetize the prostate with local anesthesia just like you would anesthetize the mouth for dental work. With local block of the prostate, biopsies can be obtained with a lot less discomfort. There is now a general tendency for doctors to obtain more biopsy cores initially to diagnose the cancer earlier and avoid multiple biopsy sessions.
If we can identify 80% of prostate cancers while they are still contained within the prostate and cure some of those that had spread just barely outside the prostate we should be able to cure 90% of prostate cancer if people would comply with early detection and appropriate treatment recommendations.
This slide shows how frequently cancer was missed on initial biopsies in our PSA study. We have some men who have had up to ten biopsy sessions because their PSA either remained elevated or kept getting higher despite repeated negative biopsy results. On the first biopsy session, nearly 30% were found to have cancer but even out to the sixth biopsy session, we still detected cancer in about 7% of the patients. Of the cancers detected in our screening study, only 75% were detected on the first biopsy. We didn't get near 100% detection until five biopsy sessions. The bottom line is that if a man has an elevated a rising PSA and has had a negative biopsy, it does not prove that he doesn't have prostate cancer.
Using the lower PSA cutoffs requires more patients to undergo biopsies, but the cancer will be detected earlier. Most of the cancers will be contained within the prostate, and very few will have the features of what some call "harmless" cancers.
Moving to the treatment for early prostate cancer, the most conservative, least invasive treatment for prostate cancer is so-called "watchful waiting," and I'm including dietary therapy here as well. It's important to realize that watchful waiting is only safe for older men who have both a low-grade and a low-volume prostate cancer. Therefore, if the patient is younger or has a higher-grade tumor or a higher stage tumor, watchful waiting can be dangerous. Even in appropriate candidates, 50% of the tumors will progress to require treatment within five years.
It may be possible to treat some of these patients when the tumor starts to progress, but remember that to begin with, even with the earliest diagnosis, the prostate cancer is not always contained within the prostate, and one needs to be concerned about progression of the cancer to an incurable stage while the patient is "watchfully waiting."
The gold standard of treating prostate cancer is removal of the prostate. It's a simple concept that if the cancer is contained within the prostate gland, and the prostate is removed, you've cured the cancer. Radical prostatectomy is the only treatment that actually removes the cancer. All other treatments leave the cancer in your body and depend on an outside agent to destroy the cancer. The problems with radical prostatectomy are that it is a major operation and most men fear the possible complications of impotency and urinary incontinence.
However, even with radical prostatectomy, sometimes when you think that the cancer has been completely removed, the cancer has gotten outside the prostate. One of the advantages of radical prostatectomy is if the tumor has just barely spread outside the prostate, one can still salvage many patients with postoperative radiotherapy.
I've been performing the nerve-sparing radical prostatectomy since 1983. Since the PSA test was not developed as a screening test until the early 1990's, the first seven years of that series, we didn't have as early prostate cancer detection as we now have, and if you look at my series which now includes about 3000 radical prostatectomies, overall it turns out that only 64% were contained within the prostate. But most of those patients were from the earlier part of the series. In the more recent patients, in what we call the PSA screening era, 70% to 80% of them are found to be organ-confined. In the entire series, about 17% have had recurrences. If you look at the overall survival in my series, 90% are alive and only 3% have died of prostate cancer, so there's what is called a 97% cancer-specific survival at 7 years after surgery.
I consider a patient incontinent if he has to wear any protection at all. Using that definition, at least 8% of my patients have some incontinence. But in most instances, it's what I call "normal female continence," i.e., under normal circumstances, they are continent, but if they coughed or sneezed or laughed, or sometimes moved suddenly, they might leak a drop or two of urine. Therefore, they wear a protective pad as a precaution. About 1 to 2% have severe incontinence that requires an operation to insert an artificial urinary sphincter. Return of continence is better in younger patients.
The most difficult part of radical prostatectomy is preserving potency. The result depends on the patient's age and how good the erections were before surgery. You can see that 85 to 90% of men in their forties will recover erections, but less than 50% of men in their seventies recover erections. If their erections are completely normal before surgery, there's good recovery in 80%, but if they have marginal erections to start with, you can't really expect them to do as well.
There are other complications such as blood clots that can occur in the leg or pelvic veins, heart attack, wound infection, other complications that can occur with any major operation, but the mortality rate is very low. In my series, the mortality rate is zero. In the American College of Surgeons survey, the mortality rate is 0.4%.
As I mentioned, in patients who have tumor recurrence after radical prostatectomy, postoperative radiotherapy is often effective. The way that this works is that if the PSA rises after radical prostatectomy and radiotherapy is given to the area where the prostate was, there is a 70% chance the PSA will become undetectable. In those patients whose PSA does become undetectable, there is a 70% chance that it will remain undetectable. So, 70% of 70% is roughly a 50% chance that patients who have a recurrence could still be cured by radiotherapy. This may improve more in the future with 3-dimensional conformal therapy that allows higher doses of radiation to be given with less risk of damage to the surrounding tissue. A study from the University of California suggested that if the patients had the radiotherapy before their PSA got higher than 1, then they did about as well as if they would have gotten the radiotherapy as a preventive measure immediately follow the surgery. So, the important thing about postoperative radiotherapy - don't wait until the PSA is higher than 1 before beginning treatment. The sooner you are treated, the more likely it is to be successful.
In some patients treated with radical prostatectomy the pathologist finds cancer at the margin of resection or microscopic extension of cancer outside the prostate. For these patients, the dilemma is should he just monitor the PSA level to see if it rises, or should he automatically receive postoperative radiotherapy as a preventive measure. From the cancer-control standpoint, it is better to have radiotherapy as a preventive measure. This study evaluated 76 patients who had positive margins and got radiotherapy and another 76 matched patients who didn't receive postoperative radiotherapy. The percentage of patients who were free of recurrence at 5 years was 88% in the patients who received the radiotherapy, but only 60% of those who didn't. This study shows you that if you have unfavorable findings in your pathology report, and receive radiotherapy three to four months after surgery as a preventive measure, 90% of the patients had no recurrence 5 years afterwards. However, 60% also did fine without the radiotherapy. Many patients fear the side effects of radiation and feel they don't want to take these risks unless they are sure they need radiotherapy. So they decide to take a chance and avoid postoperative radiation unless their PSA begins to rise. I usually recommend postoperative radiotherapy for patients with positive margins.
Many of you have heard about is the laparoscopic radical prostatectomy, developed largely in France and being performed at a few institutions in this country. My current assessment is that there is no material advantage in this for the patient as there is for laparoscopic removal of a gallbladder or even a kidney. I believe that the ability to preserve potency and obtain clear surgical margins is less certain with laparoscopic radical prostatectomy.
Another treatment option for early prostate cancer is primary radiotherapy. Radiotherapy can kill cancer cells and cure some patients. Radiotherapy is attractive to many patients because it is less invasive than an operation. The major drawback of radiotherapy is that about 30% to 40% of prostate cancers have at least a few cells that are resistant to radiotherapy. The radiation might destroy 99.9% of the cells, but if there are a few cells left behind, then the radiation will not eradicate the cancer. The other drawback of radiotherapy, particularly the seed implantation, is that if the seeds are not implanted with perfect geometry some areas don't receive sufficient doses of radiation such that, even if the tumor cells are sensitive to radiation, they may not get enough radiation to destroy the cancer.
The side effects of radiotherapy are related to radiation-induced injury to the rectum and bladder, which can cause diarrhea, rectal bleeding, urinary frequency and bleeding from the bladder. Rarely radiotherapy causes incontinence, and in some cases, particularly with seed therapy, long-term urinary retention. Approximately 50% of patients lose their erections within one year following radiotherapy.
A disadvantage of radiotherapy is there is no good curative salvage therapy if there is tumor recurrence. It is more risky to remove the prostate after the tissues have been damaged by radiation. It can be done, but the complication rate is ten-fold higher.
This slide shows radiotherapy results from my institution, comparing the new 3-dimensional conformal treatment technique with standard radiotherapy. The newer techniques are more effective and have fewer side effects.
The latest development in this area is intensity modulated radiotherapy, called IMRT. With conventional radiotherapy, the radiation beam passes through the patient from front to back and from side to side, producing a box-shaped radiation field in the patient's pelvis that includes not only the prostate but also a substantial volume of normal surrounding tissue. With 3-dimensional conformal therapy, and particularly intensity modulated radiotherapy, the computer can generate a curved radiation field that focuses on the tumor and reduces the radiation dose to surrounding tissues, thus reducing the side effects.
Brachytherapy is becoming a popular treatment for prostate cancer. Some of the published results with seeds are as good or better than the best published results reported for radical prostatectomy. However, there are some problems with the interpretation of these results related to how treatment success and failure are defined after brachytherapy. With radical prostatectomy, if the prostate has been removed, the postoperative PSA should be should be undetectable. If the PSA is not undetectable, then you know that the surgery has not done the job. But with radiotherapy, the PSA level slowly drifts down, sometimes "bouncing" up again due to radiation-induced prostatitis, and it's more difficult to determine whether all cancer cells have been destroyed. This slide shows the results of seed implantation from Atlanta and Seattle, and 88% had no recurrence at 5 years in one study, and 83% were free of recurrence at 10 years. However, if you used as the criteria an undetectable PSA in the same series, only 57% would be considered cured in the Atlanta group, and 55% would be considered cured in the Seattle group. So, using strict criteria for cure, the results don’t look so good. The truth is that it is not yet known whether seed implantation will prove to be as effective as radical prostatectomy. My personal view is that the seed implantation will not be as effective.
This series of patients treat with seeds in Seattle points out an intrinsic problem with seed therapy, namely that seeds alone often are ineffective. Men with low-grade, low-stage tumors (low-risk patients) were treated with seeds alone. Patients with more aggressive tumors and higher PSA levels were treated with external beam radiotherapy first and seed afterwards. When they evaluated their treatment results ten years later, the "cure rates" were paradoxically lower in the low-risk patients (66%) than in the high-risk patients (79%). The only difference was that the high-risk patients also received external beam radiotherapy.
This slide shows a series of patients treated in Seattle, many of whom were included in the other series I showed from Seattle. However, although many of the patients are the same, the results are different. The ten year recurrence-free survival rate was 85% overall, but they are better in the low-risk patients than in the intermediate- or high-risk patients. The point I want to make here is that the results reported for radiotherapy, and particularly seed therapy, may be as good or better than results of radical prostatectomy, but one has to wonder whether the criteria they are using for calling favorable results are as rigorous as they should be.
Cryoablation, or freezing the prostate, was tried initially and then it fell out of favor, mainly because the doctors weren't being reimbursed for doing it. Recently, the procedure is reimbursed and so it is coming back to some extent. Cryoablation is another less invasive treatment prostate cancer. It involves inserting probes in the prostate gland through which liquid nitrogen is circulated. This creates an ice ball as the prostate gland is frozen. Ideally, it would freeze the whole prostate and kill every cancer cell. The real problem in performing cryoablation is that the backside of the prostate is situated adjacent to the rectum, and prostate cancer usually arises in the backside of the prostate very near to the edge of the gland. Therefore, in order to kill all prostate cancer cells, it is necessary to freeze the gland all the way out to the capsule. Attempting to do this risks freezing the rectal wall that can produce a fistula between the rectum and the prostate, a horrible complication. To avoid this, doctors don't allow the freezing to extend to the edge of the prostate. As a result, there often is a "rind" of viable tissue left in the peripheral part of the prostate that is under-treated, and the cancer can come back. Recently, the technology has been improved, but if you look at the statistics in terms of the PSA-free recurrence rates and the long-term biopsy studies showing whether cancer was present, they are not very good. If cryoablation fails, it is very difficult to remove the prostate; so salvage therapy following cryoablation also is limited. Most patients become impotent following cryoablation.
The last treatment I will discuss is hormonal therapy that is sometimes used in treating local disease. Although hormonal therapy can control prostate cancer for long periods of time (I have one patient who has been in complete remission for 19 years on hormonal therapy), it is never curative and eventually the prostate cancer will come back. The other downside of hormonal therapy are side effects: impotency, hot flashes, muscle loss, osteoporosis, loss of energy, and weight gain. Because of these side effects, many men opt for intermittent hormonal therapy so that they get a respite from the side effects. It's not really known whether intermittent hormonal therapy is as effective as continuous hormonal therapy. This is currently under study. Also, whether hormonal therapy should be given early in the course of disease or whether it can be postponed is also a matter of debate.
Recently, a drug company sponsored a study in which men who had been treated with radical prostatectomy, radiotherapy, or watchful waiting were randomized to receive high-dose Casodex hormonal therapy or placebo. As expected, Casodex therapy delayed tumor recurrence. Accordingly, some doctors are recommending adjuvant Casodex therapy. However, Casodex is expensive, and many men either do not need it or could safely wait until treatment is necessary.
In closing, I want to re-emphasize is that no single treatment is best for all patients. Surgery is the most effective treatment for younger, healthier men with a high likelihood of having localized prostate cancer. Radiotherapy might be preferable for older men with more underlying medical problems or more advanced disease. Hormonal therapy is best for men who are elderly or for other reasons are not candidates for a major operation or radiotherapy. Watchful waiting may be the most prudent choice for men whose life expectancy is limited and whose tumor does not appear to be aggressive. Sometimes, the best treatment for the tumor is not the best treatment for the patient. Therefore, in selecting treatment, one must consider the stage and Gleason grade of the tumor, the patient's age and general health, the PSA level, how many biopsy cores were positive, the digital rectal exam findings, and the patient's concerns about the potential side effects of various treatments. Optimal treatment selection should be tailored to the individual needs and goals of the patient.
Thank you very much for your attention.