For a long time now, I have wanted to provide an essay to prostate cancer patients on how I became a specialist in treating prostate cancer. At no time in my early medical career did I set out to become an ‘expert’ in the treatment of prostate cancer, but I could not be happier now that my medical oncology practice is devoted to the diagnosis, evaluation, and treatment of prostate cancer at all stages. This journey has been personally rewarding, and I find that my patients are highly educated, highly motivated, and provide a level of interaction that exceeded my expectations as a young physician.
I knew I wanted to be a doctor since the third grade. I was always inclined towards science and medicine, and for many summers did pure laboratory research at Washington University in St. Louis where I grew up. After graduating from Indiana University with a degree in chemistry, I applied to medical school, and was accepted back home at the University of Missouri. While I had always expected to attend Washington University, closer to my home, my mentors at Wash U. strongly advised me to consider the University of Missouri for its excellent training in clinical care; their rationale being that given my dedication to basic science, they felt the strong clinical program at UM would provide balance helping me become the physician/scientist I hoped to become. After two years of medical school at the University of Missouri, I was fortunate enough to win a Pew Foundation Fellowship at Rockefeller University in New York, studying obesity and energy metabolism. After spending a little more than one year in New York, I returned to medical school, and completed my clinical training. From there, I accepted a residency program at UCLA to do training in medicine, oncology, and hematology.
I specifically chose UCLA because it offered me acceptance into a new program that would allow me to get a Ph.D. at the same time I was learning the skills necessary to be a medical oncologist. However, in my fourth year at UCLA I had an epiphany; I realized that I could be a good scientist in the future, but that my heart truly was with patient care. I missed my stethoscope more than anything. At that point, I dropped out of my Ph.D. in molecular biology, and focused purely on patient care, with an emphasis on breast cancer. My first position after leaving UCLA was at the John Wayne Cancer Institute, a center well known for the treatment of breast cancer.
It was during the above time I began to provide weekend services (‘on-call’) for a local physician specializing in prostate cancer. This doctor was well known for his outspoken and unconventional approach to prostate cancer. At that time, his opinions on the treatment of prostate cancer mattered very little to me, as it was only my job to handle any emergencies or phone calls on weekends. However, during that period, I did begin to notice a few things about his practice that were inconsistent with what I had been told by the general community of oncologists. I became aware that most of his recommendations regarding newly diagnosed prostate cancer, while being unpopular with doctors, were not inconsistent with medical practice and published literature. My interactions with his patients demonstrated not only sound medical care, but also that he had a wonderful relationship with his patients, as well as his staff. Ultimately, for a variety of reasons, I left my practice in West Los Angeles, and joined this doctor working solely in the treatment of prostate cancer.
Quite honestly, I did not expect to be working long in this new practice, or to become a prostate cancer specialist at the time that I joined the group. I felt that as a young physician, unsure of wanting to raise a family in Los Angeles, this could be a good transition time. However, I did begin to spend a great deal of time reading all of the literature regarding the management of prostate cancer, and came upon the same realizations (these are actually facts) that my partner had come across many years before. It is as follows:
There is no evidence from randomized clinical trials to support the use of radical therapy such as surgery or radiation (or even hormone therapy) over watchful waiting for clinically-detected or PSA-detected prostate cancer. Now this statement may sound inflammatory or absolutist, but I will certainly provide the counter-argument to these statements as they do exist. However, the most remarkable issue was that we had often been castigated for his view, and yet the literature supported us completely. The world of academic ‘evidence-based’ medicine wanted to have it both ways. In the protracted arguing, the message seemed to be getting lost.
On the other side of the coin, stating there is no evidence that surgery or radiation saves lives compared to watchful waiting in prostate cancer may be an overstatement. However, only one contemporary trial exists regarding this subject, and that is the study published by Holmberg in the New England Journal of Medicine in 2002. In this study of nearly 700 men with clinically-detected (not PSA-detected) prostate cancer, patients were randomly assigned to either radical prostatectomy or watchful waiting. At a median follow-up of 6.2 years, no overall survival benefit was seen for the use of radical prostatectomy. A definitive advantage was seen in prostate cancer survival for men undergoing radical surgery, but this was offset by unexpected or unexplained deaths in the surgery arm; therefore no overall survival advantage was seen. I am confident that given a few more years, there will be an advantage to radical prostatectomy over watchful waiting in clinically-detected prostate cancer from this randomized clinical trial.
But given that these men had clinically-detected prostate cancer, not PSA-detected, and given that no immediate therapy was provided to the watchful waiting arm, I find it inconsistent with the treatment patterns here in North America. That is to say, bad therapy may be better than no therapy for men with clinically-detected prostate cancer.
In this same study, and an important aspect of my generalized approach to early prostate cancer, quality of life was measured. In the Holmberg Study, two important caveats were identified. Quality of life is significantly decreased in the areas of potency/erections and urinary incontinence (diapers) for men receiving surgery, (they also established that men with watchful waiting can also have these problems, and underscores the importance of establishing a baseline).
A more recent study from the Journal of the National Cancer Institute in September of 2004 identified severe and enduring decreases in quality of life for men receiving surgery or radiation therapy.
Specifically, five-year quality of life outcomes comparing surgery and radiation show erectile dysfunction in 80% of men receiving surgery, and 64% of men receiving radiation. Urinary incontinence, defined as the regular use of diapers, was 29% in men receiving surgery, and 4% in men receiving radiation therapy. And lastly, bowel dysfunction and fecal bother, which is often not reported in the surgical literature, was described as occurring in 20% of the surgical patients, and 29% of the radiation patients.
Dr. Ian Thompson, a well-respected academic urologist, reported in his editorial of this article on, ‘How many men would accept these risks such if they knew that often the treatment would not prevent a prostate cancer death?’
Lastly and important for my evaluation of newly diagnosed prostate cancer, it is apparent that we have highly reliable algorithms and nomograms for predicting which men may or may not be cured from radical therapies for early prostate cancer. That is to say, we can use Prostate Calculators, (www.prostatecalculator.com), Partin Tables, Kattan Nomograms, etc, to predict a variety of outcomes such as likelihood of PSA recurrence, extraprostatic disease or surgical stage. These nomograms have been validated against blinded datasets and are highly reproducible. Despite this, many physicians continue to ignore the predictive value, and still proceed with radical therapies based on the possibility of cure, rather than the probability of cure.
When I sit down for a consultation with a newly diagnosed patient, I view it as my responsibility to provide education regarding the likelihood of prostate cancer being a systemic disease and, synonymously, what is the likelihood that surgery or radiation (in any of its forms) would be a curative therapy? I suggest to my patients that they need to consider the possibility of treating prostate cancer as a chronic disease, or consider whether they can realistically pursue an attempt at curative treatment. This decision all boils down to a true understanding of the words, “probability” and “possibility.” It is certainly possible for men with clinically localized high-risk disease to “be cured”; however, the likelihood of cure is very low. Conversely, men with true low-risk prostate cancer have a very high probability of being cured with a radical local therapy, but I have difficulty recommending such treatment, given the high likelihood of side effects, and the absence of a survival advantage for treatment in low-risk disease. I do not have ￼￼￼￼to make this ultimate decision on treatment (unless specifically asked by my patient) but it is absolutely my job to give you the tools to make such a decision. I can help you determine “can I be cured?” But you need to determine on an emotional level, “Do I need to be cured?” I prefer to partner with my patient and help guide them to the treatment that is appropriate for their personality and lifestyle.
Further, appropriate evaluations of newly diagnosed prostate cancer can be quite complex. In today’s day and age, we cannot rely on PSA, clinical stage, and Gleason score by a community pathologist alone. Biopsy reports must be evaluated by an expert in prostate pathology. If a nomogram is based upon a specific Gleason score, and that Gleason score is increased, say from 6 to 7 by an expert, that will clearly change the prediction. There is good published data regarding the consistent under- grading and under-staging of prostate cancer prior to surgery or radiation. In simple terms, most doctors do not appreciate both how much cancer is there and how aggressive it may be.
Staging is another major area where we should not be relying on our clinical examination alone. If I am to examine a patient and find no abnormalities on the prostate, that would be described as stage T1c. However, if I am aware that the patient has had prostate biopsies and that, as example, two of six biopsies on the left have cancer, and two of six biopsies on the right have cancer, I can assure the patient that at surgery, he will have a minimum pathologic stage of T2b. One cannot ignore the additional information and rely solely on the clinical information.
This also leads us to the importance of number of positive biopsies or percent of core biopsy involvement in prostate biopsy specimens. Again, strong data exists for the number of positive biopsies stratifying patients into risk groups for a recurrence. What this means is, even if we believe you to be in a low-risk group, based upon expert Gleason score, clinical stage, and PSA value, if 12 of 12 biopsy specimens have cancer in them, then you are overwhelmingly likely going to experience PSA recurrence if you proceed with some form of radical therapy as monotherapy. The exact cutoff is more than 50% positive biopsies place you into a very high-risk category for systemic disease, which is synonymous with PSA recurrence.
Lastly, I think it is inappropriate to ignore our advanced imaging techniques such as endorectal MRIs with or without spectroscopy. We can certainly utilize these tools to provide appropriate staging, and to give patients a more exact estimate of tumor involvement. I do not recommend this study for patients who are confident that they are going to go ahead with surgery or radiotherapy; I recommend a study like this for patients who are unsure of which treatment to go with, so that they can have the most information possible to make their decision. I am certainly one physician who prefers to have more information, and make the decisions seemingly more difficult, rather than to go forward with limited information, and an unwarranted sense of optimism (or pessimism).
Only when all of the information is available can we make an appropriate assessment of risk status. Risk status means risk of recurrence after surgery or radiation therapy and risk status is synonymous with likelihood of PSA recurrence (usually within 4-5 years of local therapy).
So it became clear to me after seeing so-many men with PSA-only recurrence, and after seeing many patients with urinary incontinence and sexual dysfunction, that the standard approach to prostate cancer may be over-treatment for the vast majority and inadequate treatment for the minority with truly aggressive disease. It comes back to the original statement by Dr. Whitmore (the Father of Urologic Oncology) many years ago, to paraphrase, “For those men in whom cure is possible, it is not necessary, and for those in whom it is necessary, it is not possible.”
I am fond of using analogies to help explain complicated medical issues to cancer patients. Decision-making in early prostate cancer is similar gambling in Las Vegas. My job, as the medical oncologist, is to advise these gamblers, these men with early prostate cancer, on the likelihood of winning, or of the so-called likelihood of being cured (please be advised that the definition of cure is completely time dependent, and usually only stated for up to five years). For example, we can estimate that some men may have a 20% chance of being cured/winning; some men may have a 50% chance of being cured/winning, and some men may have an 80% chance of being cured/winning. With appropriate evaluations, I can make those estimations with a fair degree of accuracy. After those determinations are made, we are again faced with the two words I feel are most important in this field, “possibility” and “probability.” There is no doubt that all of the men have the possibility of winning, or the possibility of being cured. However, careful evaluation will lead us to the exact probabilities of winning.
If once you know your probability you still wish to gamble in Vegas, (or in this analogy, proceed to some form of radical local therapy), then you must approach the table. However, before you can get to the table, some individual is going to approach you and request payment to sit at the table. This payment, however, is not monetary. They are not asking for your wallet. To actually play at this table, for the possibility of winning, or the possibility of cure, you must pay ahead of time. The payment, of course, is in reduced quality of life. No one will argue that quality of life is improved after radical surgery or radiation therapy. But there is overwhelming evidence that quality of life will decline after such treatments, and this decline has been quantified by numerous authors.
Nonetheless, you may wish to pay; you may wish to subject yourself to these risks. That is your choice. And of course, I have no doubt that treatment by the best physicians at the best centers will minimize those risks, but they will, in no way, remove the risks completely.
So there you are, with your odds of winning or losing, with your payment in reduced quality of life, at the table in Las Vegas. I certainly hope you win, but you must keep in mind that no one has ever demonstrated that winning, or being cured in this case, will make you live any longer. That is, the men who lose at the table will live just as long as ￼the men who win, according to published data today. Now that is not to say that men won’t live longer. I am a strong believer in expressing both sides of the coin. Just because there is no evidence that surgery or radiation provide a survival advantage, does not mean such an advantage does not exist. However, we have not demonstrated that potential benefit to date, and if such an advantage exists, it does not exist within the first six years after surgery, and any advantage must be qualified based upon the proven reduction in quality of life.
Dr. Mark Litwin, a urologist at the UCLA Medical Center, and expert in measurements of quality of life, once wrote in an editorial about the treatment of early prostate cancer that the ultimate goal is not quantity of life, nor is it quality of life; it is quality-adjusted survival. That is, is it worth living a few years longer but with diminished quality of life, or is it worth living a few years shorter, but better quality of life? These are difficult questions with no absolute answers. However, in returning to our Las Vegas analogy, in my opinion, the only individuals who are going to win are those with the wisdom not to play.
These pages have previously been filled with discussions of intermittent triple androgen blockade followed by finasteride maintenance, as described by our office. I will not use this space today to go over all results, but only to say that there is no evidence that our treatment (like any other) provides any survival advantage over watchful waiting either. However, the use of TAB does not have any permanent side effects such as those associated with surgery or radiation. More importantly, I do not suggest that intermittent triple androgen blockade is a curative treatment for prostate cancer. There are those who believe hormone blockade could be curative but I prefer using a chronic disease management model when approaching prostate cancer. Some people feel that with younger men we should attempt a curative therapy, but I actually feel that the opposite is true. The younger men are the ones most likely to experience PSA recurrence, as they are likely to live another 20 to 30 years. It is our patients, age 65, 75, and older who are most likely to die from cardiovascular-related diseases than the younger patient. I have difficulty overall trying to find any patient for whom an attempt at curative therapy is a reasonable idea. Overall, I have suggested that using intermittent triple androgen blockade followed by finasteride maintenance is a reasonable management strategy that needs to be studied further in clinical trials. We are currently preparing a second manuscript on our long-term results (including patterns of re-treatment (14 men), men who chose delayed local therapies (6 men)), and have now been able to incorporate validated quality of life results to validate our overall treatment.
I continue to advise men that prostate cancer remains one of the most poorly understood, poorly taught, and overall “messy” areas of cancer medicine. There is very little evidence to support the treatments that any of the fine doctors amongst these pages propose. Yet there are strong opinions about treatment approaches. How are patients supposed to navigate this minefield with any confidence? I do not have the answer to that question, but will continue to provide as much education as I can to my patients on decision-making in early prostate cancer, and more so now than ever, I will continue to advocate against the use of radical prostatectomy, radiotherapy, or any of the contemporary variations.
In general, most men in North America are not interested in watchful waiting, although it remains a viable option. Certainly, there are enlightened groups of urological physicians who are advocating deferred local therapy in lieu of immediate radical therapy. I applaud this approach.
And lastly, I will continue to offer primary triple androgen blockade followed by finasteride maintenance as an alternative to radical curative therapy or watchful waiting.