Predicting Prostate Cancer’s Future Behavior

BY MARK SCHOLZ, MD


Developing an accurate prognosis, i.e., predicting how a man’s cancer is likely to behave in the future, is the first and most important step toward optimal care. Future predictions are often looked at with some suspicion. With prostate cancer, however, our power to anticipate future cancer behavior is quite accurate unless there is a lack of thoroughness in gathering information.

The Size of the Tumor
Tumor size is a universally important prognostic sign for almost all types of cancer including prostate cancer. The method for incorporating tumor size into the Anthony D’Amico’s staging system relies on the degree of PSA elevation, the tumor grade and on how the prostate "feels" with the finger of a trained practitioner. These indicators are useful but don’t incorporate information from modern imaging. Imaging provides accurate information about tumor size and the presence or absence of extracapsular extension. These are very powerful prognostic predictors and it would be foolish to disregard their importance. As things stand presently these indicators are often used to divide the low, intermediate and high risk categories into "favorable" and "unfavorable" subcategories, each with a different spectrum of recommended treatment options.


Knowing Past Treatments Tells Something about Future Prognosis
Historically, since the total number of available treatments is relatively limited, practitioners have used a sequential "trial and error" treatment methodology that administers the standard treatment options in a fairly predictable sequence. For example, it is not uncommon for men to start with surgery or radiation. When a relapse occurs, standard hormone therapy (Lupron) is often started and given intermittently or continuously. Hormone therapy usually controls the disease for an average of 10 years. When Lupron stops working, immunotherapy with Provenge is usually follows. After Provenge, more potent hormone therapy with Xtandi or Zytiga is started. If these two agents prove ineffective, chemotherapy with Taxotere or radiation with Xofigo would be considered next.

The whole point of presenting the treatment sequence described in the previous paragraph is to convey the idea that the number of previous treatments communicates important information about that patients’ future prognosis. Having "failed" Lupron, for example, bespeaks of a much more worrisome prognosis compared to the situation where Lupron continues to be effective.


Response to Lupron, The Mother of All Metrics
The quality of the "response" to Lupron is actually one of the most powerful prognostic metrics available. The degree of PSA decline after Lupron is incredibly important. How low the PSA drops after starting Lupron is called the "PSA nadir." The specific PSA threshold used to determine a "good response" is less than 0.1. Believe it or not, there is a huge difference in prognosis between a man on Lupron for six months who has a PSA of 0.1 versus a man whose PSA levels off at 1.0.

An Established History is also a Prognostic Indicator
Another somewhat obvious prognostic indicator that is often overlooked and almost never discussed in textbooks has to do with the prognosis of men who have been diagnosed years ago -- over time it is apparent that things are turning out much better than what might have been expected based on their initial indicators. For example, take the case of a man who started off with a panoply of bad indicators—tumor is in the lymph nodes and Gleason 10—but after aggressive treatment remains in remission for 5 years. The fact that things have gone well for five years counts bigtime in his favor going forward. Remember, the original prognostic predictors of a Gleason 10 were just that, predictors. No predictor is 100% accurate. Five years of established history is a stronger predictor than the original Gleason score. The fact that things have gone well for five years, strongly indicates that the future is for that individual is bright. Such individuals have "beaten the odds."

The Location of the Tumor in the Body
Another extremely important indicator of prognosis, something that even laypeople anticipate by simple common sense, is the location of the cancer in the body. Location says volumes about how things are likely to progress in the future. For example, consider the following sequence of progressively more serious cancer sites:

•Contained within the prostate
•Extended into the seminal vesicle
•Spread to the lymph nodes
•Bone metastases
•Liver metastasis

Each of these locations is very important for determining prognosis.

This short blog is just an introduction to some of the "profiling" methods utilized in generating an accurate prognosis. Space limitations preclude discussion here about other known prognostic factors such as the size of the prostate gland (discussed in a previous blog), genetic tests and PSA doubling time. The D’Amico risk categories constitute the backbone of useful prognostic information. However, the additional prognostic information beyond the D’Amico risk categories that are discussed in this blog, provide additional useful information necessary for determining an accurate prognosis. An accurate prognosis is the starting point for accurate selection of treatment.

High Cost of Pharmaceutical Agents

MARK SCHOLZ, MD

In the last five years the prostate cancer world has been blessed with some incredible pharmacetucal breakthroughs--Zytiga, Xofigo, Xtandi, Provenge and Jevtana, just to name a few.  All these new medications are proven to prolong life and improve quality of life.  In my day to day life practicing as a prostate oncologist, I have seen with my own eyes how these new medications have transformed "hopeless" situations into genuine cancer remissions.

The extremely high cost of these new pharmaceutical agents, however, is a hot topic that I have addressed in prevous blogs. A recent editorial  from the Wall Street Journal addresses this issue with uncommon wisdom and aptly points out how potentially dangerous seemingly well-intentioned efforts to control costs can end up snuffing out the new drug development process.

Please click on the link HERE to read this short and extremely well-written editorial: http://goo.gl/F7pG8w

 

A Xofigo Update

BY MARK SCHOLZ, MD

Since Xofigo was FDA approved two years ago, the doctors at Prostate Oncology—Dr. Richard Lam, Dr. Jeffrey Turner and I—have been avid users.  So this seems to be a good time to provide an informal update of our experience with Xofigo to the present time.

The clinical trial that led to Xofigo’s approval by the FDA was a prospective, placebo-controlled study demonstrating improved survival in Xofigo-treated men compared to men treated with placebo alone.  The trial showed a very low incidence of side effects and good relief for men who were suffering from bone pain.

Xofigo is made out of radium, a radioactive element. After it is injected into the blood stream it concentrates near the cancer and delivers a potent dose of radiation.  So after Xofigo is injected into the patient, it travels through the blood stream and concentrates in the irritated areas of the bone and emits radiation where the cancer is most active.  Since prostate cancer spreads almost exclusively to bone, an injection of Xofigo ends up targeting most if not all of the cancer. Radiation consists of high energy, subatomic particles that blast cellular DNA. Once the DNA of the cancer cell has been hit, the cell is rendered incapable of reproduction.  If you stop cancer reproduction you basically stop the cancer.

To almost everyone, radiation conjures up horrible visions of toxicity. Fortunately, bone marrow toxicity is rare in men because Xofigo emits a different type of radiation, “alpha particles,” rather than the standard “photon type” of external beam radiation. Alpha particles dissipate their energy over a very short distance, only a couple of millimeters. External beam radiation therapy, the type of radiation that has traditionally been relied on to kill cancer cells in the bone, needs to be used very judiciously because the radiation is “beamed” through the body to hit the target in the bone. Typically it causes irreversible damage to the surrounding bone marrow.

Over the last two years at Prostate Oncology, we have treated over 50 patients with Xofigo.  The treatment has been very well tolerated.  Occasionally, we have seen a few patients with mild diarrhea or nausea that has been easily managed with common medications. Men experiencing pain from cancer usually see either partial improvement or total resolution of their pain after one to three of the monthly treatments.

As reported from the original study that led to FDA approval, even though pain relief occurs and alkaline phosphatase (ALP) levels in the blood decline, PSA may continue to rise.  This “disconnect” between PSA and other clinical parameters such as pain and ALP can be disconcerting to doctors and patients alike.  The reason that it occurs is unclear. A similar phenomenon has been observed with another FDA-approved cancer therapy called Provenge.

Experts hypothesize that the survival advantage from Xofigo and Provenge is due to a slowing of cancer progression rather than an actual regression of the cancer. This “slowing” is powerful enough to extend patients’ lives but insufficiently powerful to consistently induce a decline in PSA.  However, in our practice at Prostate Oncology notable declines in PSA have been observed in a few patients treated with Xofigo.  One patient dropped his PSA from 50 down to zero and his PSA still remains at undetectable levels.  Another recent patient has dropped his PSA from 150 down to 8.

For the patients on Xofigo who have rising PSA levels, it is logical to consider adding another effective anticancer agent such as Xtandi, Zytiga or Taxotere.  It is encouraging to know that several studies now show that Xofigo can be safely combined with these other effective therapies.

Xofigo has been a very welcome addition to our anticancer armamentarium.  The standard FDA approved protocol consists of a course of monthly treatments continued for a total of six months.  Further trials are in progress to study the potential advantages of continuing Xofigo for longer than six months.  Our experience to date suggests that longer therapy would indeed be advantageous in some instances.

Xtandi (enzalutamide), the Star of the 10th Annual Genitourinary Meeting

BY MARK SCHOLZ, MD

The GU-ASCO meeting kicks off the first of five annual prostate cancer meetings that are on my calendar to attend every year. The other four meetings are hosted by the American Urological Association (AUA) in May, the PCRI meeting in September, the American Society of Therapeutic Radiation Oncology (ASTRO) that is also in September and the Prostate Cancer Foundation retreat (PCF) that occurs in November.  
 
Since GU-ASCO is the first meeting of the year, the new scientific research presented sets the tone for the whole Year.  This year’s meeting was dominated by the release of a report showing that Xtandi, a potent oral anti-cancer agent, prolongs life compared to placebo when administered prior to the chemotherapy drug Taxotere (a previously published study has already shown that Xtandi prolongs survival when used after Taxotere).
 
It’s exciting to see an effective pharmaceutical agent get expanded access. This will lead to a greater number of men benefiting with prolonged survival and better quality of life. The bare bones of this groundbreaking report are summarized here:
 
Abstract #1: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer. Results of the phase III PREVAIL study.
 
In this randomized, double-blind, placebo-controlled, multinational phase 3 study, chemotherapy-naive patients with metastatic hormone-resistant disease were treated with either enzalutamide or placebo.
 
Results: A total of 1,717 men were enrolled. Final results showed a significant benefit of enzalutamide over placebo with a 30% reduction in risk of death and an 81% reduction in risk of radiographic progression or death. At the time of the analysis, 28% of enzalutamide patients and 35% of placebo patients had died.
 
The findings of this study almost certainly indicate that the FDA will approve Xtandi for use prior to Taxotere and in the near future,  Xtandi will compete head to head with Zytiga and Provenge, both of which are already FDA-approved for men in the pre-chemo category.
 
The fact that FDA approval is almost guaranteed means that doctors are going to start asking a very important question:  What is the optimal way to sequence these three medications?
 
Presently there is no clear answer about whether Zytiga should be before Xtandi or vice versa. However, there are several very strong arguments that Dendreon’s product, Provenge, a medication that works by stimulating the immune system, should go first:

1.   Provenge only takes 6 weeks to administer, so there is no problem adding other anticancer agents after Provenge administration is complete.

2.   Immune treatments in general are thought to work better when initiated at an earlier stage, before the cancer becomes more entrenched and starts to suppress immune function.

3.   Provenge changes the immune system in a fashion that keeps working indefinitely after the initial 6-week treatment period is passed.

4.   Because insurance only pays for Provenge in men with rising PSA levels, starting Xtandi or Zytiga, both effective in lowering PSA, can substantially delay the initiation of Provenge.   

 

There seems to be broad consensus that Provenge should be first in line.  The real question then is, “What should come second, Xtandi or Zytiga?”

At the GU-ASCO meeting there were a number of reports, including a report from our office, that show reduced anticancer effects of Xtandi when used after Zytiga.  This is hardly surprising since the phenomena of progressively increasing cancer resistance with each cycle of therapy have been known about for 30 years. Preliminary reports also show a reduced Zytiga response-rate when it is used after Xtandi.

While these reports document that the first agent selected is likely to be used for a much longer time period than the agent that follows, so far there are no studies evaluating whether sequencing  affects overall survival.  Xtandi clearly has reduced anticancer activity after Zytiga. The same, however, has also been observed in reports evaluating Zytiga in men who have previously failed Xtandi.

The jury is still out. Until further comparative studies are performed, no one knows if there is an advantage to using Zytiga first or Xtandi first.  Presently however, I think most experts are assuming that Xtandi and Zytiga seem to have similar overall anti-cancer potency, the preference of sequencing one agent over the other to be first in line is unlikely to have a major impact on overall longevity.

Combination Immune Therapy—A Major Breakthrough

BY MARK SCHOLZ, MD

Normally it’s a rule for me in these blogs to avoid straying away from the theme of prostate cancer. I want my efforts to have a practical application for those struggling with this condition.  After all, prostate cancer is my specialty.

 

However, I am going to make a rare exception and break with my usual policy because of a stunning medical breakthrough in the treatment of advanced metastatic melanoma, a very deadly condition that until recently has been totally resistant to all forms of treatment.  The only exception has been a newly FDA-approved immunotherapy called Yervoy.

 

A month ago I wrote about the high hopes we have for immune therapy for prostate cancer.  I also wrote about a clinical trial we are conducting at Prostate Oncology Specialists that evaluates the combination of two different types of immune treatment, Provenge and Yervoy (see my blogs from March and April of this year for further details).

 

Immune therapy has tremendous potential for treating cancer since the immune system has unlimited potential to adapt to any cancer scenario.  As more and more new types of immune therapy are being discovered, it’s only logical to conduct clinical trials that combine them to see if the simultaneous use of two immune treatments will further enhance the anticancer effect.

 

The report I am so excited about was just published in the New England Journal ofMedicine (NEJM). Doctors from Memorial Sloan Kettering and from Yale evaluated the combination of two types of immune therapy in advanced melanoma—Ipilimumab (Yervoy) and Nivolumab.  In my previous blog I explained how Yervoy functions by taking the “brakes” off the immune system.  Nivolumab works in a similar fashion, but works on a different set of brakes.  (It turns out that the immune system has two separate brake systems).

 

While Yervoy by itself has already been shown to be effective for treating melanoma and is FDA approved for this purpose, Nivolumab is still going through clinical trials. Twelve weeks after the researchers administered Yervoy and Nivolumab simultaneously, one third of the patients had more than an 80% regression of all known tumors.

 

Furthermore, the side effects of giving the medicines in combination were no more severe than those encountered when either of the drugs was used by itself.

 

This report from the NEJM is very exciting because it provides proof for the concept that combining immune treatments will lead to enhanced anticancer effects. Moreover, another report of success using a combination of immune treatments was just released at the annual meeting of the American Society of Clinical Oncology (ASCO). Two-hundred and forty-five men with melanoma were treated either with Yervoy alone or with a combination of Yervoy plus Leukine.  The men treated with the combination of Yervoy plus Leukine lived 30% longer!

 

Leukine is an immune system stimulating medication that the FDA approved years ago for increasing white blood cell counts in patients treated with chemotherapy.  However, Leukine is also known to have anticancer effects as well. For example, it is used as an integral component in Provenge.  In addition, at the ASCO meeting in 2011, we published results from a trial we did in Marina del Rey in prostate cancer patients showing that Leukine plus low-dose cyclophosphamide (another immune-modulating drug) delays prostate cancer progression.

 

My dear friends and patients, I am amazed at how rapidly immunotherapy is progressing.  Not only are new and exciting medications being discovered,  innovative research evaluating combinations of these new powerful new medicines is leading to stunning cancer reversals in cases that as recently as a couple years ago were deemed totally hopeless.

 

Let me leave you with this final and encouraging thought.  The immune system is very egalitarian. Great results achieved in one type of cancer will inevitably translate into effective treatments for other types of cancer as well, including, of course, prostate cancer. The achievement of unprecedented anticancer effects with combination immune therapy in a stubborn and deadly cancer like melanoma bodes very well for significant breakthroughs to occur for prostate cancer as well. 

A New Immune Treatment Combination

BY MARK SCHOLZ, MD

In my last blog I contended that of all the different ways to treat cancer—hormone therapy, chemotherapy, radiation or surgery for example—immune therapy has the greatest potential to save lives: Only the immune system, by its very nature, has the ability to adapt to the many thousands of varieties of cancer.  Also, new breakthroughs in understanding how it works have led to real progress inharnessing the immune system to fight cancer. 

One discovery—that the immune system uses a specific type of immune cell called the “dendritic cell” to detect cancercells—led researchers at a company called Dendreon to develop a five-step process for enhancing dendritic cell function.

First the dendritic cells are filtered out of the blood for processing in the lab. Second, the dendritic cells are exposed to prostatic acid phosphatase (PAP), a protein that can be identified on the surface of almost all prostate cancer cells. Third, the dendritic cells are incubated with granulocyte macrophage cell stimulating factor (GM-CSF) which converts the dendritic cells from their dormant state into an activated form. Fourth, the activated dendritic cells are infused back into the patient’s blood. Fifth, once back in the body, the activated dendritic cells recruit the killer cells of the immune system, the T-cells, to attack the cancer cells, which are identified by having PAP on their surface.

This five-step process, called “Provenge,” is an elegant and clever way to enhance immune function. Two prospective, double-blind, placebo-controlled trials have proved the efficacy of Provenge.  However, one cannot help but wonder why—since Provenge is simply an enhancement of the immune system’s normal function—is all this artificial stimulation in the lab necessary?  Why aren’t the dendritic cells in the cancer patient’s immune system detecting the cancer cells spontaneously and recruiting T-cells to attack it?

Another breakthrough has been the discovery that a normally functioning immune system, like all the systems in our body, is tightly organized by a variety of controlling hormones. Obviously, both underactivity and over activity of any system, be it the heart, the pancreas or the immune system, can be dangerous.  Now, new research reveals that malignant cells actually manufacture and release excess amounts of controlling hormones that trick the immune system into remaining dormant.  Thus the natural process of immune system detection is directly inhibited by the cancer.

Provenge partially circumvents this problem by activating the dendritic cells outside the body in the lab. But the dendritic cells still face a hostile inhibitory environment after they are re-infused. The question arises, “Wouldn’t Provenge work even better if the immune environment in the cancer patient could be rendered more “friendly"?”

In this era of rapid technological advancement it is not surprising that amedicine designed for this specific purpose is already on the market! Yervoy, a monoclonal antibody from Bristol-Myers Squib, was FDA approved to treat malignant melanoma in 2011.   Yervoy enhances immune function by counteracting the excess amounts of suppressive hormones being released by the cancer. I heard one researcher characterize Yervoy as the most powerful method available for “taking the brakes off” the immune system.

Provenge and Yervoy used together are so attractive conceptually that the only question remaining is about the optimal method of delivery.  Yervoy, unlike Provenge, can have serious side effects.  In excess amounts it can induce the immune system to run wild and start attacking the organs in the body like the liver, thyroid and intestines. Caution dictates beginning with a small initial dosage of Yervoy.

In the study we will be conducting at Prostate Oncology Specialists in Marina del Rey the first three patients we treat will be given one-twelfth of a normal dose of Yervoy one week after the Provenge is completed.  The second group of three patients will receive a one-sixth dose of Yervoy.  The third group of three patients will get three-twelfths of a Yervoy dose. All patients will receive full-dose Provenge and will be closely monitored for disease response, immune function and for possible side effects.

Provenge and Yervoy are just two of the many exciting new methods being studied for harnessing the immune system to fight cancer.  However, to my knowledge, we at Prostate Oncology Specialists are privileged to be the first to test the effectiveness of these two exciting treatments in combination.  Our first patient is scheduled to start on trial this month. 

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.               

Happy New Year Announcement from Prostate Oncology Specialists

Jeffrey Turner, MD, Medical Oncologist, Joins Prostate Oncology Specialists in Marina del Rey, CA.

MARINA DEL REY, Ca., December 31, 2012 - Prostate Oncology Specialists is pleased to announce that Jeffrey Turner, MD has joined the prostate cancer specialist team. Dr. Turner is a board-certified internist and medical oncologist and will be specializing exclusively in prostate cancer with Mark Scholz and Richard Lam. Dr. Turner has been specializing in prostate cancer since 2009. He graduated cum laude from USC. Thereafter, he worked in research at UCLA studying infectious disease and molecular biology.  He earned his medical degree in Canada at Memorial University of Newfoundland and completed his internal medicine residency at the University of British Columbia and fellowship in medical oncology at the Medical University of South Carolina. Dr. Turner has published several articles on urologic cancers with an emphasis on prostate cancer.  He is a sub-investigator of a number of ongoing prostate cancer clinical trials.

Dr. Mark Scholz, Medical Director of Prostate Oncology Specialists commented, “Dr. Turner joins us during a time when the number of new prostate cancer treatments is exploding. He will add his expertise and knowledge to help patients make informed decisions. In 2012, we conducted clinical trials with Zytiga and Xtandi, agents that are now FDA approved.  We are presently evaluating new agents such as Curstersin, XL-184 and Ipilimumab in combination with Provenge.  We are happy to welcome a talented new member to the team who is familiar with all the many new treatment options for patients—this also includes Active Surveillance which is rapidly gaining acceptance as a viable treatment for prostate cancer.”

Active Surveillance remains very popular given the alternative risk of permanent side-effects from surgery, radiation, or cryotherapy. Dr. Turner added, “With the dramatic evolution of today's imaging techniques (including color Doppler ultrasound and MRI), Active Surveillance is best for men with Gleason 6, PSA<10, and clinical stage less than or equal to T2a.  Due to the fact that men with Gleason 6 prostate cancer have an incredibly low risk of mortality, Active Surveillance should remain a strong alternative.”
As skilled leaders in treating prostate cancer, our medical oncologists use PSA monitoring and color Doppler scanning to accurately monitor men on Active Surveillance. These techniques can detect early disease progression in men who may need to pursue treatment intervention.  

For more information about Active Surveillance or Prostate Oncology Specialists - visit: www.keepmyprostate.com or www.prostateoncology.com/activesurveillance

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. 

Provenge in 2012

BY MARK SCHOLZ, MD

Doctors finally seem to be comfortable with starting Provenge, a recently FDA approved immune therapy for prostate cancer.  Dendreon, the manufacturer of Provenge, just reported a sharp uptick in their quarterly financials, indicating that the use of Provenge is increasing as doctors increase the amount of the drug they order.

Although, Provenge has been on the market for 18 months but the medical community was slower to embrace this new treatment than was expected.  It seems that it has taken time for doctors to make peace with the fact that Provenge extends life, even though there is no lowering of PSA and very few side effects.

At Prostate Oncology Specialists, we recently completed an in-house review of the first 50 men treated with Provenge, I’ll jump right to the simple and somewhat mundane conclusion or our analysis: Provenge is relatively easy to give and side effects are uncommon.

Historically, the effectiveness of cancer treatments—like chemotherapy for example—has been closely associated with notable side effects. Side effects were often equated with effectiveness.  Even some of the new immune treatments, like Ipilimumab for example, usually have side effects. It’s ironic that patients receiving Ipilimumab on investigational trials are actually comforted when they get side effects—it confirms that they are not getting a placebo.

It’s also ironic that while doctors look for PSA decline as a measure of success, PSA has been rejected by the FDA as a method for measuring the effectiveness of drugs. The FDA demands a survival endpoint rather than changes in PSA.  (Personally, I think the FDA is crazy. I think that both PSA and survival endpoints are valid.)

Nevertheless, doctors and patients alike are confused. Their seemingly logical question is, “How can someone’s life be extended without PSA dropping?”  My explanation is as follows: When Provenge strengthens the immune system, is slows the rate of cancer growth.  Using the rise in PSA as analogous for cancer growth, Provenge slows the rate of PSA rise.

I am very comfortable with the idea that effective immune therapy slows cancer growth rather than reversing it.  This phenomenon of slowing the rate of PSA rise is exactly what we reported to the American Society of Clinical Oncology in 2010 when we presented our results with three medicines with immune activity, Leukine, Low-dose cytoxan and Celebrex.  The combination of these three agents caused substantial slowing in the rate of PSA rise.

Since Provenge is so well tolerated, the next logical step is to evaluate Provenge in combination with other immunologically active treatments.  MD Anderson is ramping up to do a trial of Provenge with full-dose Ipilimumab.  At Prostate Oncology Specialists we look forward to working with treatment options such as Provenge and Ipilimumab for our patients. Hopefully the net result will be greater than the sum of the parts.

MDV-3100—An Embarrassment of Blessings

BY MARK SCHOLZ

Every day in the office, as a practicing prostate oncologist, I confront serious problems:  PSA levels that are rising, treatments causing too many side effects, patients desperately worried about their future. And sometimes, given our limited tools, the solutions we can offer are only partial. However, every time the FDA approves a new treatment there is an excitement akin to opening gifts on Christmas morning. All of a sudden we have a shiny new tool in the tool chest to help us do a better job.

I’ve repeatedly gone on record criticizing the FDA for the inflexible format they use to approve any new drug.  They insist on survival as the only important measure of effectiveness. There has to be a better way to study new drugs than giving a placebo—an inert substance containing no active ingredient—to unfortunate people who already have a life-threatening illness. But this is the format our government demands—forcing pharmaceutical companies to prove that their new anti-cancer drug works by comparing them with sugar pills. And so the human sacrifices continue.

However, back to the good news, the spirit of Christmas morning. Medivation, the manufacturer of MDV-3100, a new drug that is estimated to be twenty times more potent than Casodex, recently reported a significant survival advantage in their study comparing MDV to  the of unfortunate souls who got placebos. In other words, Medivation cleanly jumped over the bar set by the FDA. Since MDV-3100 was not associated with any unexpected side effects, the FDA will be essentially forced to hold up its end of the bargain and release it soon for commercial use.

Some are saying that MDV is just a copycat of Zytiga, one more expensive testosterone blocking pill in an already busy marketplace. I disagree completely:

1.       Since MDV has few side effects, it can be easily combined with other popular treatments like Provenge and Taxotere.

2.       Since the mechanism of testosterone blockade is completely different from Zytiga, it’s possibly that the anticancer effects of Zytiga and MDV will multiplied if they are given together.

3.       Due to its ease of use, it will be popular with the urologists, the surgeons who are charged with managing most men with prostate cancer.

My “Christmases” seem to get better every year.  Last year the tool chest was expanded to include Zytiga, Provenge and Jevtana. And there are also some amazing new drugs waiting in the wings—Ipilimumab, Dasatinib, XL-184, Revlimid and more. We finally seem to be entering a new, hopeful era for prostate oncologists—and, most important, for their patients.

FDA Roulette

BY MARK SCHOLZ

The notoriously stingy and demanding FDA gave the go ahead for two new treatments for prostate cancer in 2010.  New approvals are rare because of the hundreds of millions of dollars required to undertake the type of studies that the FDA requires. The FDA wants studies that randomly allocate men into two comparison groups. One group gets the new medicine. The other group gets an ineffective fake called a placebo. FDA approval comes when men getting the new medicine live longer than those given the placebo.

Finding volunteers willing to participate in these types of studies is difficult. The men know there is a 50% chance they will get an ineffective placebo. Who wants to take the chance of getting a sugar pill as their treatment? Even so, some men are so desperate, they sign up, hoping to be among the lucky ones who receive the real McCoy.

These studies often run for years because the study ends when the study participants die from progressive cancer.  To find men willing to participate, the supervising companies that organize and run these studies need contractual relationships with a hundred or more study centers. Just keeping track of all these different patients, at so many different locations, over a period of several years, is in itself very costly.

Provenge is the first FDA approved treatment for prostate cancer that works by strengthening the immune system. Dendreon is the name of the company that has patented a process of harvesting immune cells out of the blood by means of a technique known as “plasmapharesis.” Plasmapharesis is a three hour process similar to dialysis that extracts immune cells from the blood. The harvested cells are then taken to a special laboratory and mixed with substances that enhance their aggressiveness against cancer.  The cells are then re-infused back into the same patient. 

Provenge’s primary appeal is the low incidence of side effects. The treatment, which does not rely on chemotherapy, is so revolutionary that at first the FDA was very skeptical. They dragged their feet for years, forcing the company to run their studies over and over.  Lo and behold, additional studies again demonstrated that Provenge-treated men were 30% more likely to be three years after their treatment with Provenge compared to the men who received a placebo. Dendreon should be commended for patiently persevering time after time when the FDA kept turning them down. Now men with prostate cancer have access to an effective treatment that has very few side effects.

The other new treatment recently approved by the FDA, Jevtana, falls into the more familiar category of chemotherapy.  Jevtana was approved in July 2010 based on a randomized survival study evaluating Jevtana compared to an older, ineffective type of chemotherapy called Mitoxantrone. 755 men were treated with either Jevtana or Mitoxantrone. The survival of men receiving Jevtana was 30% better then the men treated with Mitoxantrone.  

This remarkable achievement took some industry experts by surprise because the participants in the trial had all been treated previously and become resistant to another type of chemotherapy called Taxotere.  Historically, resistance to Taxotere has been a bad sign predicting resistance to all types of chemotherapy. Jevtana, unlike Provenge has the traditional side effects of chemotherapy such as tiredness, hair loss and increased risk for infection. Even so, reversing cancer in men with Taxotere-resistant disease is quite an accomplishment. 

The FDA finally agrees that both Jevtana and Provenge are proven to make men live longer. Studies are ongoing with these newly-approved medicines to see if combining them with other drugs can further enhance their effectiveness. In the meantime, men with prostate cancer need to be aware that these new and effective tools are available.        

Whew, It’s Over!

BY MARK SCHOLZ

I just passed my annual stress test—the Prostate Cancer Research Institute (PCRI) conference. Lots of work, but certainly worth it--we had over 700 attendees from 41 states and 9 countries.  I was proud of all the 20 speakers, and particularly grateful for the contribution of Mark Moyad, MD who did a stellar job moderating.  Dr. Moyad and I reviewed some of the conference highlights on Sunday morning. They include reports on the following:

1. PET scans improve prostate imaging according to Dr. Dusing from Kansas City University and Dr. Kwon from the Mayo Clinic.

2. National Comprehensive Cancer Network (NCCN) guidelines recommend Active Surveillance for Low-Risk prostate cancer according to Dr. Klotz from the University of Toronto.

3. Multiple new chemotherapy combinations and agents—Carboplatin, Avastin, Xeloda, Custersin and Jevtana—are active against advanced prostate cancer according to Dr. Scholz.

4. Ipilimumab, an new immune treatment from Bristol Myers Squibb can induce dramatic remissions in advanced prostate cancer according to Dr. Kwon from Mayo Clinic.

5. A variety of very promising new agents—MDV-3100, TAK-700, XL-184—are in late stage trials.  Provenge, another new agent that works by stimulating the immune system is already FDA approved according to Charles Drake from Johns Hopkins.

The PCRI also announced at the conference, the launch of the Prostate Cancer Blue Community (PCBC); a web based prostate cancer community that is overseen by the PCRI helpline.  The PCBC has discussion forums about the conference and the different types of prostate cancer that we have broken down into Shades of Blue so that men can connect with other men in their same category of prostate cancer. The PCBC can be accessed at www.pcribc.org.