Beating Prostate Cancer with Hormonal Therapy

By Charles E. (Snuffy) Myers, M.D., Founder and Medical Director, The American Institute for Diseases of the Prostate, Charlottesville, VA

Reprinted from PCRI Insights May, 2007 v 10.2

Editor’s Note: This article was excerpted from Dr. Myer’s newly published book titled, Beating Prostate Cancer: Hormonal Therapy and Diet. Dr. Myers is both a leading oncologist specializing in prostate cancer and a patient stricken with the (now undetectable) disease.

While many men will face the “conventional” treatments for prostate cancer, whether it’s radiation, surgery, or chemotherapy, it is quite likely that they will also undergo hormonal therapy in conjunction with these treatments or if these treatments fail. The parameters for failure or recurrence for these treatments vary depending on the patient, but it’s important to note that hormonal therapy can stall or even prevent recurrence for many men. In fact, as I will mention later, there are even some cases where hormonal therapy alone has been very successful in pushing prostate cancer into remission. However, many men are given a very erroneous picture of hormonal therapy – a picture that paints this form of treatment as much less effective than it actually is. This inappropriately negative picture leads many men to needless depression and hopelessness.

Importance of Optimism

The pessimist has his worst fears confirmed whereas unexpectedly good things often happen to optimists!

When I was first diagnosed, I had a very aggressive case of cancer that involved metastatic spread to my lymph nodes. I discussed my case with quite a few of my colleagues. In general, the assessment was that I almost certainly would be ill with advanced disease by five years and would likely die within ten. While I do take some satisfaction that my PSA is now undetectable more than eight years after the diagnosis, my course wasn’t easy. But the single most important thing I did was to take the attitude that I would do whatever I could to gain control over my cancer. Even if I ended up dying of prostate cancer, I wanted to know that I had done everything possible to avoid that end.

I chose a very aggressive form of treatment that involved surgically removing the lymph nodes in the back of my abdomen. I followed this procedure with external beam radiation and brachytherapy to attack the remaining cancer in my prostate and then underwent eighteen months of aggressive hormonal therapy to deprive the remaining cells of the androgens on which they thrive. I also adopted a Mediterranean heart-healthy diet and began to take several supplements that, according to current research, limit the spread of prostate cancer or reduce the risk of dying from it.

I realize that as a prostate cancer specialist I had a leg up on the typical patient, which is why I want to stress how important and empowering it is to educate yourself in a time when it’s easy to despair.

Too often, pessimism and, ultimately, depression can affect the way men view their disease, their treatment, and the success of their chosen program. In fact, over the years I’ve found myself asking if pessimism is as deadly a disease as prostate cancer itself.

This question can be answered in many ways, I think. I suppose creating some disease criteria would be helpful in answering this question. Is a disease something that affects our daily life? Is it something that at times can be so overwhelming it pervades every action until it dominates even the way we think about ourselves? Does it affect our loved ones in the process? Will it reduce years from our lives? If one uses these criteria to describe a disease then, yes, pessimism certainly qualifies. We all know people, call them cynics, realists, etc. and so on, who are constantly focused on the negative. To them, the world is a cruel and heartless place where nothing good ever happens—or where everything good in this world simply doesn’t happen to them.

Think about how much time they spend dwelling on these issues, how much energy they expend on them, and how much energy it takes just to listen to their litany of complaints about this world. Whether they feel entitled or depressed, that everything is their fault or that nothing is, this kind of thinking leads people to the same place: desperation and despair.

I do find it interesting that this idea is firmly fixed in our culture. How often have we heard that John Doe just died because “he gave up”? In contrast, the cliché “where there is a will, there is a way” also comes to mind. I deal with life and death issues everyday, and time and time again I have seen people give up and die long before they should have. In contrast, I have patients who refuse to give up even though their disease is so aggressive that their other doctors urge them to put their affairs in order. These kind of relentless optimists continually seek out new and better treatments and beat all odds. In the book “Survivor Stories”, edited by my daughter and son-in-law, you’ll find several such stories—in fact one woman received a call from a medical institution some years after she received her “death sentence” from them. “We’ve noticed that you’re still alive,” they said. “Do you mind coming in for a few tests?”

While this is purely anecdotal evidence, the medical community sees anomalies like this all the time. Is it simply optimism that keeps these people alive or is it pessimism that kills? Folk wisdom suggests that pessimism is the mistake and now it seems that the medical literature also supports this idea.

The article that triggered my thoughts on this subject appeared in the Archives of General Psychiatry in 2004 (Giltay, et al). In this Dutch study, 466 men and 475 women between the ages of 65 and 85 took a test to determine their relative optimism versus pessimism. They were then followed from 1991 to 2001. During that time, there were 397 deaths. The optimists had a death rate close to half that of the pessimists. The deaths from cardiovascular disease, largely heart attack and stroke, were down by 77% in the optimist group compared with the pessimists. There was a similar study in the journal Psychosomatic Medicine last year that showed a marked worsening in carotid atherosclerosis in pessimists compared with optimists (Mathews, et al). Finally, the Mayo Clinic reported similar results that involved following optimists versus pessimists for greater than 30 years.

How is it that optimists do better than pessimists? It appears that these two approaches to life have a very different impact on human biology. In one recent article, Steptoe, et al. measured cortisol, the major stress hormone in the body, and found that levels were lowest in those who rated themselves as happy. One key event in the evolution of heart disease is the appearance of blood clots in the major arteries. Steptoe, et al. found elevated fibrinogen levels, a major risk factor for heart disease, in those who rated themselves as unhappy.

My own observations suggest that the picture is far worse than these articles indicate. Not only do pessimists do worse medically, but also they are absolutely miserable while they wait for bad things to happen. For the optimist, time is usually passed pleasantly because he or she anticipates that whatever bad things might happen, tomorrow will most likely be good.

I am reminded of my great uncle who died at age 98. He had experienced a wide range of medical illnesses and was never able to qualify for life insurance. When he was in his 80s, I asked him the reason for his long life. He said that you can always expect to get sick. The secret was figuring out a way to get well. This is how he approached each of his many illnesses: he assumed there was a way to get well again. He managed to practice dentistry from his mid 20s until his retirement at age 93. Every day for more than 70 years, he walked one mile from his home to his office and then back home each evening. During that time, he dealt with thyroid and prostate cancer, heart attack, pacemaker implantation, hypertension and a severe case of giardiasis (an intestinal disorder). After each challenge, he would marshal his resources and bounce back. He only stopped practicing dentistry when his visual acuity declined to the point where he could no longer perform.

Sometimes pessimism is just a manifestation of an underlying depression. If this is the case, I think these papers strongly support actively treating depression. This may involve drugs. For example, I have had considerable success with both Welbutrin and Lexapro as treatment for the depression that commonly develops when men are on hormonal therapy. You also need to be aware that exercise can markedly lessen depression in many people. Vitamin D and sunlight exposure also greatly influence mood. It has long been known that exposure to sunlight can lessen depression in many people. Now it appears that a good deal of that is due to vitamin D.

Nevertheless, a portion of pessimism is not founded in depression but in an approach to life, which is based on diminished expectations. And it’s hard not to let disappointments get you down when you see others thriving around you. Life may be full of disappointments for all of us, but by focusing on this, aren’t you creating a self-fulfilling prophecy in which your only consolation is that you happened to be right in the middle of a catastrophe? Remember: the pessimist has his worst fears confirmed whereas unexpectedly good things often happen to optimists!

At this point, we should note that many times it is the patient’s physician who is the cause of pessimism on the part of the patient. This is the reason why it is important for physicians dealing with cancer patients to be as accurate as possible in providing a patient with estimates of time free of cancer as well as overall survival. Unfortunately, with hormonal therapy many patients are given prognostic information that is very inaccurate and inappropriately pessimistic.

It is an unfortunate fact that in some circles, just like Rodney Dangerfield, hormonal therapy gets no respect. However, the clinical trials show that hormonal therapy can be an extremely effective treatment for prostate cancer at various disease stages. Yet there are more misconceptions about hormonal therapy than any other area of prostate treatment. For the most part, these misconceptions paint a pessimistic picture of hormonal therapy’s effectiveness and often lead to an unfounded sense of hopelessness in many patients. These misconceptions often lead patients to avoid effective methods of controlling their diseases. But why are there so many misunderstandings about hormonal therapy? Well, I think the problem has its root in the fact that the pace of prostate cancer research has been so overwhelming that it is impossible for any one physician to keep up with everything published on the disease. Physicians tend to read only those prostate cancer papers that directly relate to their own specialty. In other words, surgeons tend to read about advances in surgery, radiation therapists about radiation, and medical oncologists about chemotherapy. Unfortunately, while each of these specialists may administer hormonal therapy, none make it a central focus of their practice. Let’s talk about some of the common problems I see.

Two Common Myths About Hormonal Therapy

#1 Responses Only Last 18 months

This is one of the more persistent myths in the field and I can’t understand how it gained such wide circulation among patients and physicians. As far as I can tell, the idea dates from a paper published in 1989 by David Crawford. Crawford conducted a large, randomized controlled trial comparing Lupron alone to Lupron + Flutamide (Eulexin).

The patients on this trial had been diagnosed with prostate cancer prior to the advent of PSA screening and therefore had more advanced prostate cancer than generally seen today. Dr. Crawford and his colleagues classified patients according to whether they had advanced, moderate, or minimal disease according to the standards of that time. Those with advanced disease had widespread bone metastases and suffered from significant symptoms. On average, these patients became resistant to hormonal therapy after just over eight months. Those with moderate disease had cancers that spread throughout the skeleton, but did not have any symptoms. These patients became resistant to hormonal therapy after an average of 18 months.

I think the common assumption that hormonal therapy lasts 18 months comes from the results seen in the patients with what was then considered moderate disease—or widespread bone metastases without symptoms. But there are many reasons why it is inappropriate to generally cite this statistic. First, even in 1989, 18 months was just the average. In Crawford’s study, half the patients continued to respond after 18 months and a significant percentage were responding at five years. I think it’s important for patients with widespread bone metastases to know that there is a chance their cancers may continue to respond to hormonal therapy even after the oft-cited 18-month mark. Still, time and again, I see men arrange their financial affairs with the assumption that they won’t live another five years only to find themselves impoverished when they’re lucky enough to beat the 18-month figure. But there is no reason you have to have the average result!

The second problem with the 18-month figure is that I see it quoted to men who do not have widespread bone metastases. Some physicians even cite the figure to men who only have lymph node metastases or even simply a rising PSA after radical prostatectomy or radiation therapy. Of course, these patients don’t have nearly as extensive prostate cancers as those in the Crawford study and are likely to continue to respond to hormonal therapy for many years to come.

Why do patients with lymph node metastases do so much better if they’ve had their prostate gland removed? The best study to shed light on this issue is one from MD Anderson Cancer Hospital published in 1994 by Zagars, et al. In this study, patients with lymph node spread were placed on hormonal therapy and followed until their disease recurred. (Note that these men did not have their prostate glands removed.) Once a patient’s disease recurred, researchers recorded where hormone-resistant [link to disease emerged. In more than half the cases, hormone-resistant disease first emerged in the prostate gland. I think this makes sense. Hormone-resistance is the result of a mutation, a change in the genetic material in the cell, which allows the prostate cancer cell to grow at very low testosterone levels. In general, mutations are random events that occur once in every 1-10 million cells.

Thus, all other things being equal, you would expect hormone resistance to emerge at locations where there are a large number of cancer cells. (At the time of diagnosis, patients with lymph node metastases still usually have the largest bulk of cancer in their prostate glands.) If the prostate gland is an important source of hormone resistant prostate cancer, then removing the prostate gland should improve hormonal therapy’s results. And indeed, at the Mayo Clinic, Horst Zincke makes it a practice to remove the prostate glands in those patients with lymph node metastases. His results represent a dramatic improvement in the duration of hormonal therapy response. A randomized controlled clinical trial published in 1999 by Edward Messing confirms the Mayo Clinic results. These results are shown in Figures 1-3. As you look at these graphs, reflect on how wrong it is to tell patients that they will fail hormonal therapy in 18 months.

The first of these (figure 1) shows the overall survival of men in the Messing trial. Those placed on hormonal therapy immediately after surgery did better than those patients not put on hormonal therapy until they had recurrent disease. Of course, these curves only go out to 10 years and, as we have already discussed, this is still too early to see the full benefit of hormonal therapy. Additionally, men with prostate cancer tend to be older and can well die of heart disease, stroke, kidney disease or other cancers instead of prostate cancer.

Figure 1. Overall Survival of all Trial Participant

Figure 2 shows the prostate cancer specific survival. Remember, all the men on this trial had lymph node metastases. Again, those who went on hormonal therapy immediately after surgery did quite well with close to 90% alive at 10 years. However, even those without immediate hormonal therapy did well. Again, the point is that 10 years is still early to see the full impact of hormonal therapy on lymph node metastatic disease.

Figure 2. Prostate Cancer-Specific Survival Rates

Figure 3 shows the proportion of patients who have not yet developed progressive prostate cancer. As shown, at the seven year point close to 80% of the men with surgery followed by early hormonal therapy are still free of disease recurrence, and, no relapses were seen after the fifth year. In contrast, those who had surgery only are doing less well.

Figure 3. Proportion of Participants Who Have Not Yet Developed Progressive Prostate Cancer

These results emphasize several points. First, remember this graph the next time someone tells you that hormone resistance develops in 18 months. Second, it emphasizes that hormonal therapy is quite effective when it is started at a time when the amount of cancer is small. To put this into perspective, Dr. Walsh from Johns Hopkins has recently published his overall results with radical prostatectomy. Dr. Walsh is well known to be careful about whom he operates on and that he chooses patients most likely to benefit from surgery. In his series, less than 80% of these patients were in remission at 10 years – that’s not much better than this group of men with lymph node metastases treated with surgery and immediate hormonal therapy.

Since 1989, PSA screening has revolutionized the field of prostate cancer diagnosis and treatment: we’re diagnosing cancers earlier and earlier. In most studies of PSA screening, widespread metastatic disease is often identified only in the first and sometimes the second year of screening. Thereafter an overwhelming majority of patients have cancers that appear to be confined to the prostate gland. In fact, the worst situation you are likely to see with any frequency is patients with disease that has extended outside the prostate capsule to seminal vesicles or pelvic lymph nodes. Even these patients can be treated successfully with hormonal therapy combined with aggressive external beam radiation therapy plus brachytherapy.

What this means is that more often than not, a man considering hormonal therapy has a PSA increasing after surgery or radiation therapy and metastases too small to see with a CT or MRI scan. We have no published series that accurately reports response duration in these patients, but I suspect that they would do as well or better than those with documented lymph node metastases after surgical removal of the prostate gland. Indeed, one series has been presented in abstract form, but not published. Drs. Scardino and Scher reviewed their experiences at Memorial Sloan Kettering in New York City and found that half of their patients were still responding at the 10-year mark. Based on my clinical experience, this result looks to be approximately correct.

Table 1 represents my best estimate of the average time to hormone-refractory cancer at various stages of spread. Again, as you see, the 18-month figure only applies to a relatively small group of men, not the vast majority of those patients seen today.

I conclude that hormonal therapy is far more durable than generally thought. In fact, almost all men who recur after radical prostatectomy or radiation therapy will continue to respond to hormonal therapy after five years and about half will continue to respond after ten years. The only major exception would be those men who have rapidly growing cancers.

#2 Hormonal Therapy Doesn’t Kill Prostate Cancer Cells

Over the last several years, a growing number of patients tell me they’ve been told that hormonal therapy doesn’t kill prostate cancer cells, but just stops cancer growth and artificially lowers the PSA test, thereby fooling us into thinking cancer cells have actually died. I find this myth very strange. Time and again, hormonal therapy clinical trials have reported shrinkage of measurable cancer metastases. Depending on the clinical trial, up to 30% of patients enter complete remission, which means that all detectable prostate cancer has disappeared! How can you enter a complete remission without having killed prostate cancer cells?

On the other hand, some patients do not respond to hormonal therapy and among those patients, hormonal therapy hasn’t killed a significant number of prostate cancer cells. It is also true that the PSA test can be deceptive during hormonal therapy. With the drop in testosterone that follows the administration of Lupron, Zoladex, Eligard or Trelstar, PSA values often decline to below 0.05 ng/ml by the third month. If you look carefully at the extent of the cancer at that point, you may see little or no change in the size of the cancer in the prostate gland, lymph nodes, or other sites. Instead, the size of the cancer at these sites gradually decreases over a period of many months, often taking 9-12 months to reach maximum shrinkage. However, it is true that a rapid and dramatic fall in the PSA is a good thing and indicates that the patient is a good candidate for subsequent, equally dramatic cancer shrinkage.

Who is not likely to have a durable response to hormonal therapy? Researchers are in the midst of identifying specific genes that determine success or failure of treatment for prostate cancer. In a few years, we will be able to specify sets of genes that govern success or failure of hormonal therapy. At present, we live in a more primitive world where we make predictions on how the cancer appears under the microscope and how it behaves in the patient. Two factors appear to have been well established as favoring more rapid development of hormone resistance. First, cancers with a Gleason of 8 or greater favor early appearance of hormone resistance. Second, rapidly growing cancers, especially where the PSA doubling time is more rapid than three months, tend to develop hormone resistance earlier. When the patient has both a Gleason of 8 or more and a rapid PSA doubling time, hormone resistance can appear in a much shorter period of time than is seen in the more common forms of prostate cancer. At present, early introduction of chemotherapy is being studied as a possible alternate option for these patients and early results look quite promising.

Conclusions

With any life-threatening illness, it is easy to despair, but you need not despair. While I was 55 at the age of my diagnosis, the prospect of living just five or ten more years did not appeal to me, as you might imagine. Instead, I undertook a treatment based on defying the then-current expectations of the prostate cancer industry. And with an undetectable PSA after more than eight years, I believe that this treatment regimen was indeed successful. I fervently hope that this article and my book will provide reasons for optimism all the men who are more in the dark than I was after my diagnosis. With any luck, you will find yourself in a safer and happier place.

Editor's Note: Dr. Myers' book is available at www.prostateforum.com or by calling 800-305-2432.

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