Hormone Blockade for Early-Stage Prostate Cancer

MARK SCHOLZ, MD

Being medical oncologists rather than surgeons—and being more impressed by the toxicity of surgery than by its effectiveness—my partners and I hypothesized back in the early 1990s that since testosterone inactivating pharmaceuticals (TIP) are powerful enough to reverse metastatic disease, they should be even more effective against early-stage disease.

Clinical Experience with TIP for Early Stage
In 2011, we published a scientific article in the Clinical Genitourinary Cancer detailing the twelve-year outcome for 73 men who embarked on TIP as primary therapy. In this group of men the average PSA was 9 and the average Gleason score was 7 (intermediate grade). Most of the men had tumors in their prostate large enough to be felt by digital rectal examination. Twenty-one of them maintained a low PSA indefinitely with a single course of TIP—they never needed a second cycle.

Another group of 24 men required periodic repeat cycles of TIP to keep their PSA less than five. In the remaining 28 men, after one or more cycles of TIP, the decision was made to undergo treatment with surgery, seeds or radiation.  However, the average time to treatment was 6.2 years after the first cycle of TIP. Only three of those 28 men ever relapsed after treatment. In summary, this study showed that initial remissions with TIP were universal and that even if the remission was not permanent, treatment with more radical therapy was delayed many years.

In 2012, we published another scientific study in The Prostate, in which we evaluated the effect of 12 months of TIP in 102 men. Twenty-two men were in the Low-Risk category, 30 were Intermediate-Risk and 50 were High-Risk. The median PSA was 7.8 and the median Gleason score was 3 + 4 = 7. The attainment of a clear biopsy after TIP followed by a sustained 7- year remission occurred in forty-five men. The likelihood of durable remission was dependent on the risk category: 82% of Low-Risk, 47% of Intermediate-Risk and 25% of men with High-Risk required no further treatment.

Monitoring TIP’s Effectiveness
One of the beauties of TIP is how easily its anti-cancer effects can be monitored with PSA. Although there is much debate about using PSA for cancer screening, PSA is an amazingly accurate tool for monitoring treatment response. In a study we published in Urology in 2007, we showed that more than 95% of men with newly-diagnosed disease drop their PSA to less than 0.05 within eight months of starting therapy. It’s a rare for cancers to continue producing PSAs above a threshold of 0.05 after six months of TIP therapy.  However, when these rare cancers occur, i.e. when an elevated PSA nadir occurs, it is a flashing sign that aggressive multi-modality therapy should be instituted.

What about Side Effects?
So what is the catch?  To this point TIP sounds like a very logical way to initiate treatment. Even if the disease is not arrested altogether, it delays progression for many years. And men who select TIP as initial therapy can always “jump ship” and undergo radiation or surgery. Delaying surgery or radiation with their potentially irreversible side effects makes sense considering the acclerating pace of medical progress. In this rapidly changing environment, postponing irreversible treatment for even five years is unquestionably an attractive proposition.

The catch is that while TIP side-effects are manageable, they are not trivial. Without attention to diet, notable weight gain occurs. Without regular resistance training and weight lifting, significant muscle weakness will ensue. While on treatment, the majority men lose their sex drive. A loss of sex drive is, however, different than impotence. With medications such as Viagra and Cialis most men on TIP can have erections sufficient for intercourse. Sex can be enjoyed, but it is not sought after with the usual male verve. There is also the potential for additional side effects such as breast enlargement, osteoporosis and hot flashes. As dire as these sound, they are preventable with common medications such as Femara, Prolia and progesterone. However, the side effects are cumulative and become more prominent the longer TIP treatment is continued.

Final Thoughts
Some men are concerned that their cancer will progress if “real treatment” like surgery or radiation is delayed. They forget that surgery and radiation only eradicate the “friendly types” of prostate cancer, the ones that remain contained in the gland. The real danger lies in the possibility of microscopic metastasis. Radiation and surgery have no effect whatsoever on cancer that has already spread. Only TIP circulates throughout the entire body attacking early-stage micro-metastasis in the lymph nodes or bones.

In my next blog, I will be discussing a new, more powerful type of TIP that has recently been approved by the FDA. The enhanced effectiveness of this new drug may enable a shorter course of treatment. And since testosterone levels in the blood remain normal throughout, the risk of lingering side effects should be eliminated.   

Fifteen Days and Counting

RALPH BLUM

It’s now been three weeks of IMRT—that’s fifteen radiation treatments. The procedure is simple enough, which is somehow reassuring. I arrive Monday through Friday afternoon at the Arizona Avenue Emergency Entrance of St. John’s Health Care Center. If possible, I find a parking place on the street. Otherwise, it’s Valet Parking, with Fernando smiling broadly, “Don Rafael!” and a five-dollar deduction if I have my parking ticket stamped in the treatment center.

Making my way to the radiation unit was a challenge. On my first visits, I used my cane to hobble down a corridor lined with photographs of previous Directors of St. John’s, and stretching most of the way from Arizona to Santa Monica. Then I took an elevator down to the Garden Floor (No “Basements” here). Then another long trek, passing beneath a Commemorative Tablet honoring Vasek Polak, the prostate cancer patron (his money built the IMRT unit). Finally I arrived at the “PRESS HERE” electronic door into the Radiation wing.

With my bad knees, even using a cane, it was a long haul. And since I’ll be making it for 44 days in all, I reckoned it was time for a change. I remembered seeing a clutch of black canvas-backed, metal-framed wheelchairs just inside the door from Valet Parking. So I appealed to “Transportation.” After only a few minutes, a blue-smocked, gray haired lady volunteer arrived, settled me into a wheel chair, and wheeled me down to Radiation. And so it would continue—someone to wheel me down, someone to wheel me back, for the remaining treatments.

What an improvement! I never thought about wheelchairs before—I was never wheelchair “bound” before IMRT. I learned that the first known “dedicated” wheelchair (called an “invalid’s chair”) was made in 1595 for Phillip II of Spain by an unknown inventor. I bless his unknown memory as the wheels turn and I ride at ease.

The aide parks me just inside the door of the bright comfortable waiting room. There are usually several people sitting in the lounge chairs, reading out of date magazines, waiting for a friend or family member to return from treatment. Or waiting to stretch out and fit into their own treatment mold.

The routine is the same every day. I sit in the waiting room until collected by James or another radiation tech or nurse, who takes me into the changing area and hands me a blue, open–in-the-rear, cotton garment to change into. Then I am escorted through the Ops area (Computer screens frozen on the vast Ion Chamber, charts and graphs, the empty, waiting slide) and into the treatment room with its futuristic cyclorama unit where I am settled into my custom-fitted lower body mold. My three tattoos are aligned with the brilliant green, needle-thin laser beam, followed by my daily MRI. And when all is aligned,  the canned Tchaikovsky starts up, and the whirring of gears announces that the flow of electrons has begun. The zapping itself is surprisingly brief: my prostate is receiving radiation for barely two minutes.

Once a week, Dr. Chaiken and one of the nurses interviewed me: Any pain? Blood in urine? Rectal discomfort? Urinary problems? They each repeat the same questions. Covering the bases twice, just to make sure. I had no unwelcome side-effects. More important, I now believe,  I never felt anxious. Never felt a sliver of doubt. I knew that all would be well.

Only twenty-nine or thirty treatments to go.

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. 

Tattooed, Targeted and Zapped

BY RALPH BLUM

Today, at 1:20PM in St. John’s Hospital basement radiation wing, a bright, airy facility managed by friendly, competent techs, nurses and other staff members, I was given the first of 44 doses of Intensity Modulated Radiation Therapy aka IMRT, under the outstanding supervision of Dr. Lisa Chaiken.

 

As explained by the Cancer Treatment Centers of America, IMRT uses advanced software to plan a precise dose of radiation based on tumor size, shape and location. A giant, revolving, computer-controlled machine called a linear accelerator (“Linac” by the techs) delivers radiation in “sculpted” or “carved” doses that match the exact 3D geometrical form of the prostate. In my case, since the cancer is already in the left seminal vesicle, that will also be included in the precisely targeted radiation field.

 

With IMRT, the radiation oncologist can adjust the intensity of radiation beams across the treatment area as required with laser confirmed accuracy. (You can actually see the brilliant green light of the laser emanating in a needle thin beam from the treatment room walls.) This translates as the ability to deliver higher radiation doses than by traditional radiation therapy methods, while minimizing exposure to healthy tissues.

 

What concerned Jeanne most was:  Will I be tired after treatments, so that she should be there to drive me home. Somehow, I just don’t expect to feel excessive fatigue, though we will judge that as the treatments proceed. However, it is worth mentioning that, because the treatment effect is “cumulative,” somewhere around the mid-point (say around 22+ treatments) I may begin to feel fatigue.

 

To prepare me for the procedure, thanks to Jamie, one of the radiology techs, I now have three minute “tattoo” crosses inked right, left and center onto my pelvis, and covered with transparent patches to protect them. The tattoos will serve in the coming treatments to set up and align the path of the Linac.

 

As I settled into the specially tailored plastic body mold, I found myself feeling quite comfortable with the procedure: no anxiety, no dwelling on possible negative side effects (urinary distress, anal irritation up to and including the charming condition referred to in doc speak as “hamburger ass”).

 

When I left the treatment room that housed the 12 foot tall linear accelerator, I was offered a daily treatment time of 9AM for the remaining 43 does of IMRT, However, just to be safe, I rejected that in favor of a regular daily time of 4:20PM. That way, if there is a build up of fatigue, it will not have a negative impact on my entire day.  Anyway, I am ready to put myself in the hands of Dr. Chaiken and her experienced team.

 

Ready to? Seems I already have.

Dying for a Biopsy?

MARK SCHOLZ, MD

Screening for prostate cancer is big business. The PSA blood test, first implemented in the late 1980s, resulted in a doubling in the number of new cases, from 100,000 a year to more than 200,000 annually. The cost of simply diagnosing prostate cancer—after adding up doctor, lab and pathology charges—easily surpasses a billion dollars annually.

Cancer is diagnosed by a specially-trained doctor, a pathologist, who examines the prostate tissue under a microscope. Tissue is extracted by needle biopsy, a procedure that is performed in a doctor’s office. The patient lies on his side and an ultrasound probe is inserted into the rectum. Then after Novocain is injected, 12 to 14 tissue samples are removed using a spring-loaded needle gun that is fired in a grid pattern over the surface of the prostate . The tissue samples are then transported to the pathologist who determines whether or not cancer is present.

Over a million men undergo a prostate biopsy each year. Immediate biopsy at the first sign of PSA elevation has been the standard approach for more than 30 years. However, this policy needs to be reconsidered. Last year the US Preventative Services Task Force reconfirmed their strong warning against PSA screening, pointing out that it leads directly to an egregious degree of overtreatment in men with microscopic amounts of harmless low-grade prostate cancer.  The problem is that surgery and radiation induce shockingly high rates of permanent sexual dysfunction and loss of urinary control. These are distressingly serious problems when considering that treatment is frequently unnecessary in the first place.

Until recently, the needle biopsy procedure itself was perceived as being reasonably safe. However, two just-released studies indicate that it is nowhere near as innocuous as most physicians had assumed.  For example, at the American Urology Association meeting in May, doctors from Memorial Sloan Kettering reported that infectious complications requiring hospitalization occur 2.8% of the time.* In a separate study at the American Society of Clinical Oncology meeting, Dr. Boniol from the International Prevention Research Institute reported that 1.3 deaths occurred for every 1,000 men who undergo biopsy. To put this latter finding in perspective, Dr. Boniol commented, “This prostatic biopsy mortality would occur earlier than any benefit from a screening program and could reverse any potential gain from screening…”

Fortunately, there is an alternative to immediate biopsy.  MRI scanners can guide a biopsy needle directly to the area of the prostate gland where the disease is located, thus allowing a reduction in the number needle biopsies by 90%.  While there are drawbacks to this new technology—it requires special training and the equipment is expensive—the risk of serious infections should be much lower.

Change is often resisted by the status quo, especially when it involves a major shift in reimbursement patterns.  Doctors who do random prostate needle biopsies will likely view these technological advancements with suspicion. Even so, the 30-year old methodology of puncturing the prostate with multiple random needle sticks is overdue for replacement. Noninvasive MRI imaging technology to detect prostate cancer is a far more sensible way to evaluate men with rising PSA levels. 

*Abstract 1244 -The Impact of Repeat Biopsies on Infectious Complications in Men with Prostate Cancer on Active Surveillance: a Prospective Study