What is the Most Exciting New Treatment for Prostate Cancer?

BY MARK SCHOLZ, MD

As a medical oncologist specializing in prostate cancer, the question I am asked by patients almost daily is, “What new treatments are coming for prostate cancer?” Fortunately, there are so many new developments I am able to give answers that vary depending on the stage (or Shade, to use PCRI terminology) of the person asking, since they are usually interested in developments relevant to their specific situation.

However, if I am asked a slightly different question—“What type of new technology has the greatest potential for saving lives?”—my answer will always be the same for every patient: Immune therapy.  Let me explain why.

Before the intricate complexity of cancer biology was recognized—through the amazing work of thousands of biochemical researchers—people were hoping a single magic bullet could be discovered that would cure cancer.  That hope has been dashed because we now know there are innumerable variations of what we call “cancer.” Waiting for the discovery of a single type of treatment universally effective against all types of cancer is quite naive.

However, there is one intrinsic capacity in our bodies that successfully parries millions of different attacks on our health: the immune system. Therefore, if a cure for the myriad of different cancer types exists, it will probably result from successfully harnessing this incredible system.

One fallacy believed by almost all patients is that their cancer is the result of a weak immune system. Their logic is that their immune system somehow has to be weak considering that the cancer has not been kept under control. Actually, if we are going to speak figuratively about the immune system, the problem is better characterized as an issue of blindness rather than one of weakness.

Early success in using the immune system to overcome scourges such as polio caused cancer researchers to study vaccine type methods for stimulating the immune system to attack cancer,unfortunately with only modest results. The problem is that cancer cells have mechanisms that enable them to hide from the immune system.

The fairly recent discovery of this capacity for cancer to cloak itself represents both good news and bad. Without a specific target to attack, simply making the immune system “stronger” is useless. The good news is that a properly directed immune system can and will eradicate cancer.

Prostate cancer is one of the few types of cancer for which an immune therapy has been approved by the FDA. Dendreon, the company that manufactures the immune treatment called Provenge, has developed technology to remove and purify dendritic cells, the specific immune cells in the body that can detect cancer.  Once in the lab the dendritic cells are “force fed” with a cancer-specific protein. After being reinjected into the body, these invigorated immune cells recruit additional cells of the immune system that specifically focus their attack on the cancer cells displaying that cancer-specific protein.

Double-blind, placebo-controlled trials show Provenge slows cancer progression and prolongs survival just as well or even better than other standard treatments such as chemotherapy or second-line hormonal therapy. None of these treatments consistently eradicate cancer.  They do, however, act to keep it in check for a period of time.

To obtain better results the next logical step is combining one form of immune therapy—Provenge—with some other immune therapy with the hope of further enhancing the anti-cancer effect. My next blog will discuss a new study we are conducting in my clinical practice at Prostate Oncology Specialists using Provenge in combination with “Yervoy,” a monoclonal antibody from Bristol-Myers Squib. Generically Known as ipilimumab, Yervoy is an FDA-approved immune treatment shown to prolong life in people with metastatic melanoma.  Yervoy functions by “taking the brakes” off the immune system.

Sound exciting?  We think so.               

Provenge Treatment for Prostate Cancer

BY MARK SCHOLZ, MD

In 2010, Provenge was approved by the FDA, the first approved prostate cancer treatment that functions by enhancing the immune system.  Over the last couple of years Provenge has been gaining popularity with oncologists and urologists as well as with patients. What has been surprising to me is how slowly doctors and patients have warmed up to the idea of using the immune system to fight prostate cancer. For years my patients have been taking handfuls of Graviola, Shitaki mushrooms, Pau de Arco and Esiac tea because of unsubstantiated claims of immune enhancement. Yet, when the FDA approved an effective immune treatment that prolongs life I was surprised that my patients needed to be convinced to use it. 

Why, you might ask, is there any hesitation in the first place?  Well, Provenge is certainly different from other anticancer therapies at least in one very distinctive way:  Whereas the effectiveness of most treatments is signaled by a drop in PSA, PSA levels usually don’t decline after Provenge.  Having supervised more than a hundred Provenge-treated men, I have certainly seen exceptional cases with dramatic PSA declines. However, this is not the general rule. Most of the time PSA continues rising after Provenge. So people start wondering, if PSA is not dropping, how can Provenge prolong survival?  People forget that even though Provenge is administered over a six-week period, once the immune system is activated, it keeps functioning indefinitely; it’s the gift that keeps giving for the rest of your life.  Therefore, even if Provenge only slows disease growth slightly, the inhibitory effect keeps accumulating over time. So over a period of years, even a mild effect can become substantial.

If the hypothesis that Provenge is inducing a mild, long-lasting anticancer effect is correct, men take Provenge at an earlier stage (who have a longer projected survival) should receive a bigger survival benefit than men treated at a later stage. To test this thought, Dendreon, the manufacturer of Provenge, analyzed data from the original studies that led to FDA approval. Please note:  the researchers did not compare the survival of men treated earlier versus the survival of men treated later.  Obviously, men treated at an earlier stage live longer.  No, what they did is compare survival of Provenge-treated men with earlier-stage disease with similar-stage placebo-treated men.  They did the same analysis (Provenge-treated men versus placebo-treated men) in men with later-stage prostate cancer and in men with disease “in between” early and late stage.  Early stage—low-intermediate stage, high-intermediate stage and late stage—was defined by PSA levels of less than 22, 22-50, 50-134, and greater than 134 respectively. The table below summarizes the results of their analysis.

	Patients Grouped by Baseline PSA
	≤22	22–    50	50–134	>134
Number patients	128	128	128	128
Survival  months:
Provenge	41.3	27.1	20.4	18.4
Placebo	28.3	20.1	15.0	15.6
Survival Difference:	13.0	7.1	5.4	2.8

 As can be seen from the table, all groups that were treated with Provenge showed a survival advantage compared to the same stage men treated with placebo.  However, when Provenge was given at an earlier stage, the survival advantages became larger. Men with the earliest stage (PSA < 22) lived 13 months longer than similar stage men who were placebo-treated. Men with advanced stage only lived a couple months longer than advanced-stage placebo-treated men. 

This pattern of improved survival with earlier stage disease seems to fit the hypothesis that the inhibitory effect of Provenge results in a progressively longer survival when its effects are allowed to accumulate over a longer lifespan.  Based on this data one would logically conclude that Provenge induces the biggest benefits when administered at the earliest possible stage.  In the real world, where Provenge is only covered by insurance for men who are hormone resistant and have metastases, men on Lupron who have a rising PSA should be vigilantly monitored with scans such as Prostascint, C11 acetate PET and Sodium Fluoride PET scans every 6 months to detect metastatic disease at the earliest possible stage. 

Let’s Hear Those Treatment Options Again

BY RALPH BLUM

Some things not only bear repeating, they require it. Every year, in spite of all the progress made in the past half century, approxiametly another quarter of a million men are diagnosed with prostate cancer and face the daunting challenge: What treatment, if any, would be best for me? What treatment would be the least likely to put me at risk for side effects more serious than the disease itself?

Choosing a treatment plan that you can live with is an essential part of coping with prostate cancer, it is a tough decision to make.  All too often, there is no clear-cut “best” treatment, and you will get differing opinions from specialists. Your urologist will have a natural bias toward surgery (that is, after all, his specialty), a radiation oncologist’s bias will be toward radiation. Then too, friends and family will have different stories to tell that will further confuse you. Complicating the complex decision making process is the fact that all prostate cancer treatments have significant side effects. One thing is certain: the decision you make significantly alter the quality of the rest of your life.

After your doctor has evaluated the test results and you know the grade and stage of your cancer, there are other factors to consider. The first is your life expectancy, and this, of course, depends on your general health. If you have no other serious health problems and you are likely to live at least ten or more years, chances are your doctor will recommend more aggressive treatment. However, age is also a major factor, and doctors are often reluctant to pursue aggressive treatments with men older than 70 or 75, especially if the cancer is not fast growing. All the more reason to consider possible negative side effects of any treatment you choose.

Unless your PSA is rising fast, or “doubling,” I cannot repeat too often that there is no reason to rush into treatment that you might live to regret. You have to navigate a complex diagnosis, and you need to gather as much information as you can and consider all possible options before deciding which treatment is  the right one for you.

 And here’s something I learned early on: No matter how much you trust your doctor, you should get a second opinion, preferably from a medical oncologist who specializes in prostate cancer. Someone who is familiar with all the available reatments, who isn’t pushing one treatment over others, and who will give you an unbiased opinion.

If you have a low-risk or intermediate-risk cancer, the main treatment options to consider are watchful waiting (also termed “Active Surveillance”), surgery, radiation, and hormone therapy. Each has its risks and benefits and you need to investigate all of them-thoroughly. If, however, your cancer is high risk or more advanced, your treatment plan will be more complicated. Yourr options may well include a combination of these therapies, as well as chemotherapy, immune therapy, and gene therapy.

In a state of major shock after your diagnosis, you may be inclined to accept whatever treatment your doctor recommends. However keep in mind that it is very difficult for doctors who treat prostate cancer regularly not to have strong feelings that favor their own specialty. You are the one who has to live with the results if the treatment doesn’t work out well, and therefore it is you who must have the final say regarding which course to take. Never forget: if you have to get cancer, prostate cancer is the best kind to have because in the great majority of cases it is slow growing, and not only manageable but curable.

In my case, I was convinced that my prostate cancer was the tortoise and not the hare; that it was no more threatening than chronic asthma, and that I would die with it, not from it.  Now almost a quarter of a century has passed. Except for a year of hormone blockade a decade ago, I have stuck with the practice of Active Surveillance.

From everything I have seen and experienced, there are a few questions I would want answered if I were making a treatment decision today. Here they are:

What new drugs and/or treatments are on the horizon? What’s in the testing stage? How promising does it look? How long are we talking about before it comes on line?

Can I reasonably take the chance, given the degree of aggressiveness of my cancer, that waiting will result in my having a better quality of life?

Given the decision I finally make, what are the odds of my being cured?

And finally, if you are thinking about Active Surveillance, here is perhaps least discussed consideration: 

Have I got the temperament to live with even a small  amount of cancer in my body?
 

The answer to that last question is, for most men, the pivot upon which their decision must swing.  So face it. Answer it.  And then, depending on your answer, make your decision.

Why Choosing Treatment for Prostate Cancer is so Difficult

BY MARK SCHOLZ, MD

Selecting the right treatment for prostate cancer is unbelievably challenging. With other cancers, where survival is paramount, the choice is simple—do everything that can be done! But with prostate cancer, quality-of-life considerations play a much larger role, since the treatments available at this time can seriously impact the quality of your life. For some men, once their type of prostate cancer is determined, choices are somewhat easier. For example, Low-Risk prostate cancer is relatively harmless and can be safely monitored. Treatment is often deferred because the cure is worse than the disease. Decisions about treating High-Risk prostate cancer are also fairly straightforward. Most experts agree that treatment with combination therapy is appropriate. The men faced with the biggest dilemma, however, are the 60,000 to 80,000 men diagnosed every year with Intermediate-Risk prostate cancer. 

All too often, prostate cancer treatment causes some degree of impotence and incontinence.  Who wants to face sexual dysfunction unless it is absolutely required for survival? Men with Intermediate-Risk disease often feel like they are in limbo because withholding treatment for their cancer is slightly risky, but so is the treatment.  

The situation is even more confusing because if you talk to men who have already been through treatment, some seem to have weathered surgery or radiation just fine. Unfortunately, if you keep inquiring, you will come across men who feel their lives have been ruined. Men reflecting on these issues face a hard reality: choosing one of the existing treatment options can immediately destroy quality of life, while forgoing immediate treatment means having to live with the ongoing possibility that delaying treatment might someday translate into fewer years of life.

Even after careful analysis, lingering questions are inevitable, since the very best that medical science can offer is an estimate of risk. The ambiguity of these circumstances, however, leaves a lot of room for personal preference. Once a man is thoroughly educated about all his options, he, rather than the physician, is in the best position to select treatment.  After all, he is the one who will spend the rest of his life living with the consequences.

Still, there is good reason to expect things to change, hopefully in the near future. Effective ongoing research is progressing rapidly in the areas of imaging, genetics, immune therapy, and targeted pharmaceuticals. The fact that prostate cancer, in the majority of cases, is a slow-growing condition, also works to the patient’s advantage.  Every year that goes by we are one step closer to less toxic solutions. As Ralph and I always emphasize, “If waiting makes sense, time is on your side.”

*See the What’s Your Type brochure at PCRI.org for a full explanation of the difference between Low, Intermediate and High-Risk prostate cancer